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Alan N. Engelman, PhD


Researcher


Researcher

  • Professor of Medicine, Harvard Medical School

Contact Information

  • Office Phone Number(617) 632 4361
  • Fax(617) 632 4338

Bio

Dr. Engelman received his PhD in 1990 from Tufts University School of Medicine and his postdoctoral training at the National Institute of Diabetes, Digestive, and Kidney Diseases. He joined DFCI in 1995, where he conducts research on the mechanism of HIV-1 integration and teaches PhD candidates in the graduate program in virology at Harvard Medical School.

Location

Dana-Farber Cancer Institute
450 Brookline Avenue
Center for Life Sciences 1010
Boston MA, 02215
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Research



Retroviral DNA integration



Our studies focus on the mechanism of human immunodeficiency virus type 1 (HIV-1) integration, an essential step in the viral lifecycle. Retroviruses encode their own integrase protein, and our research borrows from numerous disciplines, including molecular virology and structural biology, to understand mechanistic details of integrase function. Integrase active site inhibitors have been in the clinic since 2007, but until recently their mode of action was largely speculative. Novel X-ray crystal structures of the related spumavirus integrase with its DNA substrate yielded unprecedented details of the structural basis of retroviral DNA integration and, moreover, established how the inhibitors work. Lentiviruses like HIV-1 preferentially target active genes during integration. We established that an interaction between integrase and the cellular chromatin binding protein lens epithelium-derived growth factor (LEDGF) plays a significant role in HIV integration targeting.



We have recently solved the 3-dimensional structure of the LEDGF/p75 integrase-binding domain (IBD) by NMR spectroscopy, as well as the x-ray structure of the IBD bound to the integrase catalytic core domain, the first structure of a host protein bound to a retroviral enzyme. Other studies have elucidated the LEDGF/p75 binding pocket on integrase as a sensitive binding site for allosteric inhibitors, unveiling a new location for targeting of second-generation integrase inhibitors. Current approaches include screening chemical libraries to identify small molecule inhibitors of the protein-protein interaction to evaluate their potential to block HIV-1 replication in cell culture.



Zhu Y, Wang X, Forouzmand E, Jeong J, Qiao F, Sowd GA, Engelman AN, Xie X, Hertel KJ, Shi Y. Molecular Mechanisms for CFIm-Mediated Regulation of mRNA Alternative Polyadenylation. Mol Cell. 2018 Jan 04; 69(1):62-74.e4.
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Puray-Chavez M, Tedbury PR, Huber AD, Ukah OB, Yapo V, Liu D, Ji J, Wolf JJ, Engelman AN, Sarafianos SG. Multiplex single-cell visualization of nucleic acids and protein during HIV infection. Nat Commun. 2017 Dec 01; 8(1):1882.
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El Ashkar S, Schwaller J, Pieters T, Goossens S, Demeulemeester J, Christ F, Van Belle S, Juge S, Boeckx N, Engelman A, Van Vlierberghe P, Debyser Z, De Rijck J. LEDGF/p75 is dispensable for hematopoiesis but essential for MLL-rearranged leukemogenesis. Blood. 2018 Jan 04; 131(1):95-107.
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Hoyte AC, Jamin AV, Koneru PC, Kobe MJ, Larue RC, Fuchs JR, Engelman AN, Kvaratskhelia M. Resistance to pyridine-based inhibitor KF116 reveals an unexpected role of integrase in HIV-1 Gag-Pol polyprotein proteolytic processing. J Biol Chem. 2017 Dec 01; 292(48):19814-19825.
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Alvarez FJD, He S, Perilla JR, Jang S, Schulten K, Engelman AN, Scheres SHW, Zhang P. CryoEM structure of MxB reveals a novel oligomerization interface critical for HIV restriction. Sci Adv. 2017 Sep; 3(9):e1701264.
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Yamashita M, Engelman AN. Capsid-Dependent Host Factors in HIV-1 Infection. Trends Microbiol. 2017 Sep; 25(9):741-755.
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Sugimura R, Jha DK, Han A, Soria-Valles C, da Rocha EL, Lu YF, Goettel JA, Serrao E, Rowe RG, Malleshaiah M, Wong I, Sousa P, Zhu TN, Ditadi A, Keller G, Engelman AN, Snapper SB, Doulatov S, Daley GQ. Haematopoietic stem and progenitor cells from human pluripotent stem cells. Nature. 2017 05 25; 545(7655):432-438.
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Lesbats P, Serrao E, Maskell DP, Pye VE, O'Reilly N, Lindemann D, Engelman AN, Cherepanov P. Structural basis for spumavirus GAG tethering to chromatin. Proc Natl Acad Sci U S A. 2017 May 23; 114(21):5509-5514.
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Engelman AN, Cherepanov P. Retroviral intasomes arising. Curr Opin Struct Biol. 2017 Dec; 47:23-29.
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Wang W, Zhou J, Halambage UD, Jurado KA, Jamin AV, Wang Y, Engelman AN, Aiken C. Inhibition of HIV-1 Maturation via Small-Molecule Targeting of the Amino-Terminal Domain in the Viral Capsid Protein. J Virol. 2017 May 01; 91(9).
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Grawenhoff J, Engelman AN. Retroviral integrase protein and intasome nucleoprotein complex structures. World J Biol Chem. 2017 Feb 26; 8(1):32-44.
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Ballandras-Colas A, Maskell DP, Serrao E, Locke J, Swuec P, Jónsson SR, Kotecha A, Cook NJ, Pye VE, Taylor IA, Andrésdóttir V, Engelman AN, Costa A, Cherepanov P. A supramolecular assembly mediates lentiviral DNA integration. Science. 2017 01 06; 355(6320):93-95.
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Lu YF, Cahan P, Ross S, Sahalie J, Sousa PM, Hadland BK, Cai W, Serrao E, Engelman AN, Bernstein ID, Daley GQ. Engineered Murine HSCs Reconstitute Multi-lineage Hematopoiesis and Adaptive Immunity. Cell Rep. 2016 12 20; 17(12):3178-3192.
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Zurnic I, Hütter S, Rzeha U, Helbig R, Stanke N, Reh J, Müllers E, Hamann MV, Kern T, Gerresheim GK, Lindel F, Serrao E, Lesbats P, Engelman AN, Cherepanov P, Lindemann D. Correction: Interactions of Prototype Foamy Virus Capsids with Host Cell Polo-Like Kinases Are Important for Efficient Viral DNA Integration. PLoS Pathog. 2016 Oct; 12(10):e1005956.
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Patel D, Antwi J, Koneru PC, Serrao E, Forli S, Kessl JJ, Feng L, Deng N, Levy RM, Fuchs JR, Olson AJ, Engelman AN, Bauman JD, Kvaratskhelia M, Arnold E. A New Class of Allosteric HIV-1 Integrase Inhibitors Identified by Crystallographic Fragment Screening of the Catalytic Core Domain. J Biol Chem. 2016 Nov 04; 291(45):23569-23577.
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Zurnic I, Hütter S, Rzeha U, Stanke N, Reh J, Müllers E, Hamann MV, Kern T, Gerresheim GK, Lindel F, Serrao E, Lesbats P, Engelman AN, Cherepanov P, Lindemann D. Interactions of Prototype Foamy Virus Capsids with Host Cell Polo-Like Kinases Are Important for Efficient Viral DNA Integration. PLoS Pathog. 2016 Aug; 12(8):e1005860.
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Zerbato JM, Serrao E, Lenzi G, Kim B, Ambrose Z, Watkins SC, Engelman AN, Sluis-Cremer N. Establishment and Reversal of HIV-1 Latency in Naive and Central Memory CD4+ T Cells In Vitro. J Virol. 2016 09 15; 90(18):8059-73.
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Deng N, Hoyte A, Mansour YE, Mohamed MS, Fuchs JR, Engelman AN, Kvaratskhelia M, Levy R. Allosteric HIV-1 integrase inhibitors promote aberrant protein multimerization by directly mediating inter-subunit interactions: Structural and thermodynamic modeling studies. Protein Sci. 2016 Nov; 25(11):1911-1917.
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Saito A, Henning MS, Serrao E, Dubose BN, Teng S, Huang J, Li X, Saito N, Roy SP, Siddiqui MA, Ahn J, Tsuji M, Hatziioannou T, Engelman AN, Yamashita M. Capsid-CPSF6 Interaction Is Dispensable for HIV-1 Replication in Primary Cells but Is Selected during Virus Passage In Vivo. J Virol. 2016 08 01; 90(15):6918-35.
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Saito A, Ferhadian D, Sowd GA, Serrao E, Shi J, Halambage UD, Teng S, Soto J, Siddiqui MA, Engelman AN, Aiken C, Yamashita M. Roles of Capsid-Interacting Host Factors in Multimodal Inhibition of HIV-1 by PF74. J Virol. 2016 06 15; 90(12):5808-23.
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Lesbats P, Engelman AN, Cherepanov P. Retroviral DNA Integration. Chem Rev. 2016 Oct 26; 116(20):12730-12757.
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Serrao E, Cherepanov P, Engelman AN. Amplification, Next-generation Sequencing, and Genomic DNA Mapping of Retroviral Integration Sites. J Vis Exp. 2016 Mar 22; (109).
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Rasheedi S, Shun MC, Serrao E, Sowd GA, Qian J, Hao C, Dasgupta T, Engelman AN, Skowronski J. The Cleavage and Polyadenylation Specificity Factor 6 (CPSF6) Subunit of the Capsid-recruited Pre-messenger RNA Cleavage Factor I (CFIm) Complex Mediates HIV-1 Integration into Genes. J Biol Chem. 2016 May 27; 291(22):11809-19.
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Feng L, Dharmarajan V, Serrao E, Hoyte A, Larue RC, Slaughter A, Sharma A, Plumb MR, Kessl JJ, Fuchs JR, Bushman FD, Engelman AN, Griffin PR, Kvaratskhelia M. The Competitive Interplay between Allosteric HIV-1 Integrase Inhibitor BI/D and LEDGF/p75 during the Early Stage of HIV-1 Replication Adversely Affects Inhibitor Potency. ACS Chem Biol. 2016 05 20; 11(5):1313-21.
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Ballandras-Colas A, Brown M, Cook NJ, Dewdney TG, Demeler B, Cherepanov P, Lyumkis D, Engelman AN. Cryo-EM reveals a novel octameric integrase structure for betaretroviral intasome function. Nature. 2016 Feb 18; 530(7590):358-61.
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Sowd GA, Serrao E, Wang H, Wang W, Fadel HJ, Poeschla EM, Engelman AN. A critical role for alternative polyadenylation factor CPSF6 in targeting HIV-1 integration to transcriptionally active chromatin. Proc Natl Acad Sci U S A. 2016 Feb 23; 113(8):E1054-63.
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Serrao E, Engelman AN. Sites of retroviral DNA integration: From basic research to clinical applications. Crit Rev Biochem Mol Biol. 2016; 51(1):26-42.
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Nuñez JK, Harrington LB, Kranzusch PJ, Engelman AN, Doudna JA. Foreign DNA capture during CRISPR-Cas adaptive immunity. Nature. 2015 Nov 26; 527(7579):535-8.
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Wang H, Shun MC, Dickson AK, Engelman AN. Embryonic Lethality Due to Arrested Cardiac Development in Psip1/Hdgfrp2 Double-Deficient Mice. PLoS One. 2015; 10(9):e0137797.
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Fontana J, Jurado KA, Cheng N, Ly NL, Fuchs JR, Gorelick RJ, Engelman AN, Steven AC. Distribution and Redistribution of HIV-1 Nucleocapsid Protein in Immature, Mature, and Integrase-Inhibited Virions: a Role for Integrase in Maturation. J Virol. 2015 Oct; 89(19):9765-80.
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Maskell DP, Renault L, Serrao E, Lesbats P, Matadeen R, Hare S, Lindemann D, Engelman AN, Costa A, Cherepanov P. Structural basis for retroviral integration into nucleosomes. Nature. 2015 Jul 16; 523(7560):366-9.
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Serrao E, Ballandras-Colas A, Cherepanov P, Maertens GN, Engelman AN. Key determinants of target DNA recognition by retroviral intasomes. Retrovirology. 2015 Apr 30; 12:39.
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Nuñez JK, Lee AS, Engelman A, Doudna JA. Integrase-mediated spacer acquisition during CRISPR-Cas adaptive immunity. Nature. 2015 Mar 12; 519(7542):193-8.
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Engelman A, Cherepanov P. Retroviral Integrase Structure and DNA Recombination Mechanism. Microbiol Spectr. 2014 Dec; 2(6).
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Slaughter A, Jurado KA, Deng N, Feng L, Kessl JJ, Shkriabai N, Larue RC, Fadel HJ, Patel PA, Jena N, Fuchs JR, Poeschla E, Levy RM, Engelman A, Kvaratskhelia M. The mechanism of H171T resistance reveals the importance of Nd-protonated His171 for the binding of allosteric inhibitor BI-D to HIV-1 integrase. Retrovirology. 2014 Nov 25; 11:100.
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Matreyek KA, Wang W, Serrao E, Singh PK, Levin HL, Engelman A. Host and viral determinants for MxB restriction of HIV-1 infection. Retrovirology. 2014 Oct 25; 11:90.
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Fribourgh JL, Nguyen HC, Matreyek KA, Alvarez FJD, Summers BJ, Dewdney TG, Aiken C, Zhang P, Engelman A, Xiong Y. Structural insight into HIV-1 restriction by MxB. Cell Host Microbe. 2014 Nov 12; 16(5):627-638.
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Kvaratskhelia M, Sharma A, Larue RC, Serrao E, Engelman A. Molecular mechanisms of retroviral integration site selection. Nucleic Acids Res. 2014; 42(16):10209-25.
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Li M, Jurado KA, Lin S, Engelman A, Craigie R. Engineered hyperactive integrase for concerted HIV-1 DNA integration. PLoS One. 2014; 9(8):e105078.
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Serrao E, Krishnan L, Shun MC, Li X, Cherepanov P, Engelman A, Maertens GN. Integrase residues that determine nucleotide preferences at sites of HIV-1 integration: implications for the mechanism of target DNA binding. Nucleic Acids Res. 2014 Apr; 42(8):5164-76.
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Maertens GN, Cook NJ, Wang W, Hare S, Gupta SS, Öztop I, Lee K, Pye VE, Cosnefroy O, Snijders AP, KewalRamani VN, Fassati A, Engelman A, Cherepanov P. Structural basis for nuclear import of splicing factors by human Transportin 3. Proc Natl Acad Sci U S A. 2014 Feb 18; 111(7):2728-33.
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Wang H, Shun MC, Li X, Di Nunzio F, Hare S, Cherepanov P, Engelman A. Efficient Transduction of LEDGF/p75 Mutant Cells by Gain-of-Function HIV-1 Integrase Mutant Viruses. Mol Ther Methods Clin Dev. 2014 Jan 08; 1.
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Engelman A, Cherepanov P. Retroviral Integrase Structure and DNA Recombination Mechanism. Microbiol Spectr. 2014; 2(6):1-22.
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Jurado KA, Engelman A. Multimodal mechanism of action of allosteric HIV-1 integrase inhibitors. Expert Rev Mol Med. 2013 Nov 26; 15:e14.
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Matreyek KA, Yücel SS, Li X, Engelman A. Nucleoporin NUP153 phenylalanine-glycine motifs engage a common binding pocket within the HIV-1 capsid protein to mediate lentiviral infectivity. PLoS Pathog. 2013; 9(10):e1003693.
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Matreyek KA, Engelman A. Viral and cellular requirements for the nuclear entry of retroviral preintegration nucleoprotein complexes. Viruses. 2013 Oct 07; 5(10):2483-511.
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Ballandras-Colas A, Naraharisetty H, Li X, Serrao E, Engelman A. Biochemical characterization of novel retroviral integrase proteins. PLoS One. 2013; 8(10):e76638.
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Engelman A, Kessl JJ, Kvaratskhelia M. Allosteric inhibition of HIV-1 integrase activity. Curr Opin Chem Biol. 2013 Jun; 17(3):339-45.
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Feng L, Sharma A, Slaughter A, Jena N, Koh Y, Shkriabai N, Larue RC, Patel PA, Mitsuya H, Kessl JJ, Engelman A, Fuchs JR, Kvaratskhelia M. The A128T resistance mutation reveals aberrant protein multimerization as the primary mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem. 2013 May 31; 288(22):15813-20.
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Jurado KA, Wang H, Slaughter A, Feng L, Kessl JJ, Koh Y, Wang W, Ballandras-Colas A, Patel PA, Fuchs JR, Kvaratskhelia M, Engelman A. Allosteric integrase inhibitor potency is determined through the inhibition of HIV-1 particle maturation. Proc Natl Acad Sci U S A. 2013 May 21; 110(21):8690-5.
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Koh Y, Ballana E, Este J, Engelman A. Polymorphic LEDGF/p75 variants support efficient HIV-1 infection ex vivo. AIDS. 2013 Feb 20; 27(4):665-7.
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Shah VB, Shi J, Hout DR, Oztop I, Krishnan L, Ahn J, Shotwell MS, Engelman A, Aiken C. The host proteins transportin SR2/TNPO3 and cyclophilin A exert opposing effects on HIV-1 uncoating. J Virol. 2013 Jan; 87(1):422-32.
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Koh Y, Wu X, Ferris AL, Matreyek KA, Smith SJ, Lee K, KewalRamani VN, Hughes SH, Engelman A. Differential effects of human immunodeficiency virus type 1 capsid and cellular factors nucleoporin 153 and LEDGF/p75 on the efficiency and specificity of viral DNA integration. J Virol. 2013 Jan; 87(1):648-58.
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Krishnan L, Engelman A. Retroviral integrase proteins and HIV-1 DNA integration. J Biol Chem. 2012 Nov 30; 287(49):40858-66.
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Wang H, Jurado KA, Wu X, Shun MC, Li X, Ferris AL, Smith SJ, Patel PA, Fuchs JR, Cherepanov P, Kvaratskhelia M, Hughes SH, Engelman A. HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75 knockout cells but does not contribute to the antiviral activity of a potent LEDGF/p75-binding site integrase inhibitor. Nucleic Acids Res. 2012 Dec; 40(22):11518-30.
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Matreyek KA, Oztop I, Freed EO, Engelman A. Viral latency and potential eradication of HIV-1. Expert Rev Anti Infect Ther. 2012 Aug; 10(8):855-7.
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Kessl JJ, Jena N, Koh Y, Taskent-Sezgin H, Slaughter A, Feng L, de Silva S, Wu L, Le Grice SF, Engelman A, Fuchs JR, Kvaratskhelia M. Multimode, cooperative mechanism of action of allosteric HIV-1 integrase inhibitors. J Biol Chem. 2012 May 11; 287(20):16801-11.
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Engelman A, Cherepanov P. The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol. 2012 03 16; 10(4):279-90.
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Ambrose Z, Lee K, Ndjomou J, Xu H, Oztop I, Matous J, Takemura T, Unutmaz D, Engelman A, Hughes SH, KewalRamani VN. Human immunodeficiency virus type 1 capsid mutation N74D alters cyclophilin A dependence and impairs macrophage infection. J Virol. 2012 Apr; 86(8):4708-14.
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Li X, Koh Y, Engelman A. Correlation of recombinant integrase activity and functional preintegration complex formation during acute infection by replication-defective integrase mutant human immunodeficiency virus. J Virol. 2012 Apr; 86(7):3861-79.
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Matreyek KA, Engelman A. The requirement for nucleoporin NUP153 during human immunodeficiency virus type 1 infection is determined by the viral capsid. J Virol. 2011 Aug; 85(15):7818-27.
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Yan N, O'Day E, Wheeler LA, Engelman A, Lieberman J. HIV DNA is heavily uracilated, which protects it from autointegration. Proc Natl Acad Sci U S A. 2011 May 31; 108(22):9244-9.
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Zamborlini A, Coiffic A, Beauclair G, Delelis O, Paris J, Koh Y, Magne F, Giron ML, Tobaly-Tapiero J, Deprez E, Emiliani S, Engelman A, de Thé H, Saïb A. Impairment of human immunodeficiency virus type-1 integrase SUMOylation correlates with an early replication defect. J Biol Chem. 2011 Jun 10; 286(23):21013-22.
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Koh Y, Matreyek KA, Engelman A. Differential sensitivities of retroviruses to integrase strand transfer inhibitors. J Virol. 2011 Apr; 85(7):3677-82.
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Li X, Krishnan L, Cherepanov P, Engelman A. Structural biology of retroviral DNA integration. Virology. 2011 Mar 15; 411(2):194-205.
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Koh Y, Haim H, Engelman A. Identification and characterization of persistent intracellular human immunodeficiency virus type 1 integrase strand transfer inhibitor activity. Antimicrob Agents Chemother. 2011 Jan; 55(1):42-9.
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Krishnan L, Li X, Naraharisetty HL, Hare S, Cherepanov P, Engelman A. Structure-based modeling of the functional HIV-1 intasome and its inhibition. Proc Natl Acad Sci U S A. 2010 Sep 07; 107(36):15910-5.
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Lee K, Ambrose Z, Martin TD, Oztop I, Mulky A, Julias JG, Vandegraaff N, Baumann JG, Wang R, Yuen W, Takemura T, Shelton K, Taniuchi I, Li Y, Sodroski J, Littman DR, Coffin JM, Hughes SH, Unutmaz D, Engelman A, KewalRamani VN. Flexible use of nuclear import pathways by HIV-1. Cell Host Microbe. 2010 Mar 18; 7(3):221-33.
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Ferris AL, Wu X, Hughes CM, Stewart C, Smith SJ, Milne TA, Wang GG, Shun MC, Allis CD, Engelman A, Hughes SH. Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration. Proc Natl Acad Sci U S A. 2010 Feb 16; 107(7):3135-40.
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Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature. 2010 Mar 11; 464(7286):232-6.
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Hughes S, Jenkins V, Dar MJ, Engelman A, Cherepanov P. Transcriptional co-activator LEDGF interacts with Cdc7-activator of S-phase kinase (ASK) and stimulates its enzymatic activity. J Biol Chem. 2010 Jan 01; 285(1):541-54.
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Krishnan L, Matreyek KA, Oztop I, Lee K, Tipper CH, Li X, Dar MJ, Kewalramani VN, Engelman A. The requirement for cellular transportin 3 (TNPO3 or TRN-SR2) during infection maps to human immunodeficiency virus type 1 capsid and not integrase. J Virol. 2010 Jan; 84(1):397-406.
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Dar MJ, Monel B, Krishnan L, Shun MC, Di Nunzio F, Helland DE, Engelman A. Biochemical and virological analysis of the 18-residue C-terminal tail of HIV-1 integrase. Retrovirology. 2009 Oct 19; 6:94.
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Hare S, Di Nunzio F, Labeja A, Wang J, Engelman A, Cherepanov P. Structural basis for functional tetramerization of lentiviral integrase. PLoS Pathog. 2009 Jul; 5(7):e1000515.
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Engelman A. Mechanistic and pharmacological analyses of HIV-1 integration. Methods. 2009 Apr; 47(4):225-8.
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Belshan M, Schweitzer CJ, Donnellan MR, Lu R, Engelman A. In vivo biotinylation and capture of HIV-1 matrix and integrase proteins. J Virol Methods. 2009 Aug; 159(2):178-84.
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Yan N, Cherepanov P, Daigle JE, Engelman A, Lieberman J. The SET complex acts as a barrier to autointegration of HIV-1. PLoS Pathog. 2009 Mar; 5(3):e1000327.
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Engelman A, Oztop I, Vandegraaff N, Raghavendra NK. Quantitative analysis of HIV-1 preintegration complexes. Methods. 2009 Apr; 47(4):283-90.
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Hare S, Shun MC, Gupta SS, Valkov E, Engelman A, Cherepanov P. A novel co-crystal structure affords the design of gain-of-function lentiviral integrase mutants in the presence of modified PSIP1/LEDGF/p75. PLoS Pathog. 2009 Jan; 5(1):e1000259.
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Engelman A. Isolation and analysis of HIV-1 preintegration complexes. Methods Mol Biol. 2009; 485:135-49.
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McKee CJ, Kessl JJ, Shkriabai N, Dar MJ, Engelman A, Kvaratskhelia M. Dynamic modulation of HIV-1 integrase structure and function by cellular lens epithelium-derived growth factor (LEDGF) protein. J Biol Chem. 2008 Nov 14; 283(46):31802-12.
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Shun MC, Botbol Y, Li X, Di Nunzio F, Daigle JE, Yan N, Lieberman J, Lavigne M, Engelman A. Identification and characterization of PWWP domain residues critical for LEDGF/p75 chromatin binding and human immunodeficiency virus type 1 infectivity. J Virol. 2008 Dec; 82(23):11555-67.
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Engelman A, Cherepanov P. The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog. 2008 Mar 28; 4(3):e1000046.
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Brass AL, Dykxhoorn DM, Benita Y, Yan N, Engelman A, Xavier RJ, Lieberman J, Elledge SJ. Identification of host proteins required for HIV infection through a functional genomic screen. Science. 2008 Feb 15; 319(5865):921-6.
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Botbol Y, Raghavendra NK, Rahman S, Engelman A, Lavigne M. Chromatinized templates reveal the requirement for the LEDGF/p75 PWWP domain during HIV-1 integration in vitro. Nucleic Acids Res. 2008 Mar; 36(4):1237-46.
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Zhao Z, McKee CJ, Kessl JJ, Santos WL, Daigle JE, Engelman A, Verdine G, Kvaratskhelia M. Subunit-specific protein footprinting reveals significant structural rearrangements and a role for N-terminal Lys-14 of HIV-1 Integrase during viral DNA binding. J Biol Chem. 2008 Feb 29; 283(9):5632-41.
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Shun MC, Raghavendra NK, Vandegraaff N, Daigle JE, Hughes S, Kellam P, Cherepanov P, Engelman A. LEDGF/p75 functions downstream from preintegration complex formation to effect gene-specific HIV-1 integration. Genes Dev. 2007 Jul 15; 21(14):1767-78.
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Engelman A. AIDS/HIV. A reversal of fortune in HIV-1 integration. Science. 2007 Jun 29; 316(5833):1855-7.
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Mbisa JL, Barr R, Thomas JA, Vandegraaff N, Dorweiler IJ, Svarovskaia ES, Brown WL, Mansky LM, Gorelick RJ, Harris RS, Engelman A, Pathak VK. Human immunodeficiency virus type 1 cDNAs produced in the presence of APOBEC3G exhibit defects in plus-strand DNA transfer and integration. J Virol. 2007 Jul; 81(13):7099-110.
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Vandegraaff N, Engelman A. Molecular mechanisms of HIV integration and therapeutic intervention. Expert Rev Mol Med. 2007 Feb 26; 9(6):1-19.
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Daelemans D, Lu R, De Clercq E, Engelman A. Characterization of a replication-competent, integrase-defective human immunodeficiency virus (HIV)/simian virus 40 chimera as a powerful tool for the discovery and validation of HIV integrase inhibitors. J Virol. 2007 Apr; 81(8):4381-5.
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Raghavendra NK, Engelman A. LEDGF/p75 interferes with the formation of synaptic nucleoprotein complexes that catalyze full-site HIV-1 DNA integration in vitro: implications for the mechanism of viral cDNA integration. Virology. 2007 Mar 30; 360(1):1-5.
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Shun MC, Daigle JE, Vandegraaff N, Engelman A. Wild-type levels of human immunodeficiency virus type 1 infectivity in the absence of cellular emerin protein. J Virol. 2007 Jan; 81(1):166-72.
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Anderson JL, Campbell EM, Wu X, Vandegraaff N, Engelman A, Hope TJ. Proteasome inhibition reveals that a functional preintegration complex intermediate can be generated during restriction by diverse TRIM5 proteins. J Virol. 2006 Oct; 80(19):9754-60.
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Rahman S, Lu R, Vandegraaff N, Cherepanov P, Engelman A. Structure-based mutagenesis of the integrase-LEDGF/p75 interface uncouples a strict correlation between in vitro protein binding and HIV-1 fitness. Virology. 2007 Jan 05; 357(1):79-90.
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Maertens GN, Cherepanov P, Engelman A. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J Cell Sci. 2006 Jun 15; 119(Pt 12):2563-71.
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Diaz-Griffero F, Vandegraaff N, Li Y, McGee-Estrada K, Stremlau M, Welikala S, Si Z, Engelman A, Sodroski J. Requirements for capsid-binding and an effector function in TRIMCyp-mediated restriction of HIV-1. Virology. 2006 Aug 01; 351(2):404-19.
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Si Z, Vandegraaff N, O'huigin C, Song B, Yuan W, Xu C, Perron M, Li X, Marasco WA, Engelman A, Dean M, Sodroski J. Evolution of a cytoplasmic tripartite motif (TRIM) protein in cows that restricts retroviral infection. Proc Natl Acad Sci U S A. 2006 May 09; 103(19):7454-9.
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Turlure F, Maertens G, Rahman S, Cherepanov P, Engelman A. A tripartite DNA-binding element, comprised of the nuclear localization signal and two AT-hook motifs, mediates the association of LEDGF/p75 with chromatin in vivo. Nucleic Acids Res. 2006; 34(5):1653-65.
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Vandegraaff N, Devroe E, Turlure F, Silver PA, Engelman A. Biochemical and genetic analyses of integrase-interacting proteins lens epithelium-derived growth factor (LEDGF)/p75 and hepatoma-derived growth factor related protein 2 (HRP2) in preintegration complex function and HIV-1 replication. Virology. 2006 Mar 15; 346(2):415-26.
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Cherepanov P, Ambrosio AL, Rahman S, Ellenberger T, Engelman A. Structural basis for the recognition between HIV-1 integrase and transcriptional coactivator p75. Proc Natl Acad Sci U S A. 2005 Nov 29; 102(48):17308-13.
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Lu R, Vandegraaff N, Cherepanov P, Engelman A. Lys-34, dispensable for integrase catalysis, is required for preintegration complex function and human immunodeficiency virus type 1 replication. J Virol. 2005 Oct; 79(19):12584-91.
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Lu R, Ghory HZ, Engelman A. Genetic analyses of conserved residues in the carboxyl-terminal domain of human immunodeficiency virus type 1 integrase. J Virol. 2005 Aug; 79(16):10356-68.
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Cherepanov P, Sun ZY, Rahman S, Maertens G, Wagner G, Engelman A. Solution structure of the HIV-1 integrase-binding domain in LEDGF/p75. Nat Struct Mol Biol. 2005 Jun; 12(6):526-32.
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Lu R, Limón A, Ghory HZ, Engelman A. Genetic analyses of DNA-binding mutants in the catalytic core domain of human immunodeficiency virus type 1 integrase. J Virol. 2005 Feb; 79(4):2493-505.
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Engelman A. The ups and downs of gene expression and retroviral DNA integration. Proc Natl Acad Sci U S A. 2005 Feb 01; 102(5):1275-6.
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Devroe E, Silver PA, Engelman A. HIV-1 incorporates and proteolytically processes human NDR1 and NDR2 serine-threonine kinases. Virology. 2005 Jan 05; 331(1):181-9.
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Lu R, Limón A, Devroe E, Silver PA, Cherepanov P, Engelman A. Class II integrase mutants with changes in putative nuclear localization signals are primarily blocked at a postnuclear entry step of human immunodeficiency virus type 1 replication. J Virol. 2004 Dec; 78(23):12735-46.
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Cherepanov P, Devroe E, Silver PA, Engelman A. Identification of an evolutionarily conserved domain in human lens epithelium-derived growth factor/transcriptional co-activator p75 (LEDGF/p75) that binds HIV-1 integrase. J Biol Chem. 2004 Nov 19; 279(47):48883-92.
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Turlure F, Devroe E, Silver PA, Engelman A. Human cell proteins and human immunodeficiency virus DNA integration. Front Biosci. 2004 Sep 01; 9:3187-208.
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Maertens G, Cherepanov P, Debyser Z, Engelborghs Y, Engelman A. Identification and characterization of a functional nuclear localization signal in the HIV-1 integrase interactor LEDGF/p75. J Biol Chem. 2004 Aug 06; 279(32):33421-9.
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Byers KB, Engelman A, Fontes B. General guidelines for experimenting with HIV. Curr Protoc Immunol. 2004 May; Chapter 12:Unit 12.1.
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Lu R, Nakajima N, Hofmann W, Benkirane M, Jeang KT, Sodroski J, Engelman A, Teh-Jeang K. Simian virus 40-based replication of catalytically inactive human immunodeficiency virus type 1 integrase mutants in nonpermissive T cells and monocyte-derived macrophages. J Virol. 2004 Jan; 78(2):658-68.
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Devroe E, Engelman A, Silver PA. Intracellular transport of human immunodeficiency virus type 1 integrase. J Cell Sci. 2003 Nov 01; 116(Pt 21):4401-8.
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Lin CW, Engelman A. The barrier-to-autointegration factor is a component of functional human immunodeficiency virus type 1 preintegration complexes. J Virol. 2003 Apr; 77(8):5030-6.
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Engelman A. The roles of cellular factors in retroviral integration. Curr Top Microbiol Immunol. 2003; 281:209-38.
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Limón A, Nakajima N, Lu R, Ghory HZ, Engelman A. Wild-type levels of nuclear localization and human immunodeficiency virus type 1 replication in the absence of the central DNA flap. J Virol. 2002 Dec; 76(23):12078-86.
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Limón A, Devroe E, Lu R, Ghory HZ, Silver PA, Engelman A. Nuclear localization of human immunodeficiency virus type 1 preintegration complexes (PICs): V165A and R166A are pleiotropic integrase mutants primarily defective for integration, not PIC nuclear import. J Virol. 2002 Nov; 76(21):10598-607.
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Chen H, Engelman A. Asymmetric processing of human immunodeficiency virus type 1 cDNA in vivo: implications for functional end coupling during the chemical steps of DNA transposition. Mol Cell Biol. 2001 Oct; 21(20):6758-67.
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Nakajima N, Lu R, Engelman A. Human immunodeficiency virus type 1 replication in the absence of integrase-mediated dna recombination: definition of permissive and nonpermissive T-cell lines. J Virol. 2001 Sep; 75(17):7944-55.
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Harris D, Engelman A. Both the structure and DNA binding function of the barrier-to-autointegration factor contribute to reconstitution of HIV type 1 integration in vitro. J Biol Chem. 2000 Dec 15; 275(50):39671-7.
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Chen H, Engelman A. Characterization of a replication-defective human immunodeficiency virus type 1 att site mutant that is blocked after the 3' processing step of retroviral integration. J Virol. 2000 Sep; 74(17):8188-93.
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Brown HE, Chen H, Engelman A. Structure-based mutagenesis of the human immunodeficiency virus type 1 DNA attachment site: effects on integration and cDNA synthesis. J Virol. 1999 Nov; 73(11):9011-20.
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Chen H, Wei SQ, Engelman A. Multiple integrase functions are required to form the native structure of the human immunodeficiency virus type I intasome. J Biol Chem. 1999 Jun 11; 274(24):17358-64.
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Engelman A. In vivo analysis of retroviral integrase structure and function. Adv Virus Res. 1999; 52:411-26.
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Chen H, Engelman A. The barrier-to-autointegration protein is a host factor for HIV type 1 integration. Proc Natl Acad Sci U S A. 1998 Dec 22; 95(26):15270-4.
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Jenkins TM, Esposito D, Engelman A, Craigie R. Critical contacts between HIV-1 integrase and viral DNA identified by structure-based analysis and photo-crosslinking. EMBO J. 1997 Nov 17; 16(22):6849-59.
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Du Z, Ilyinskii PO, Lally K, Desrosiers RC, Engelman A. A mutation in integrase can compensate for mutations in the simian immunodeficiency virus att site. J Virol. 1997 Nov; 71(11):8124-32.
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Engelman A, Liu Y, Chen H, Farzan M, Dyda F. Structure-based mutagenesis of the catalytic domain of human immunodeficiency virus type 1 integrase. J Virol. 1997 May; 71(5):3507-14.
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Taddeo B, Carlini F, Verani P, Engelman A. Reversion of a human immunodeficiency virus type 1 integrase mutant at a second site restores enzyme function and virus infectivity. J Virol. 1996 Dec; 70(12):8277-84.
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Engelman A. Biochemical characterization of recombinant equine infectious anemia virus integrase. Protein Expr Purif. 1996 Nov; 8(3):299-304.
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Jenkins TM, Engelman A, Ghirlando R, Craigie R. A soluble active mutant of HIV-1 integrase: involvement of both the core and carboxyl-terminal domains in multimerization. J Biol Chem. 1996 Mar 29; 271(13):7712-8.
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Engelman A, Craigie R. Efficient magnesium-dependent human immunodeficiency virus type 1 integrase activity. J Virol. 1995 Sep; 69(9):5908-11.
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Lodi PJ, Ernst JA, Kuszewski J, Hickman AB, Engelman A, Craigie R, Clore GM, Gronenborn AM. Solution structure of the DNA binding domain of HIV-1 integrase. Biochemistry. 1995 Aug 08; 34(31):9826-33.
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Englund G, Theodore TS, Freed EO, Engelman A, Martin MA. Integration is required for productive infection of monocyte-derived macrophages by human immunodeficiency virus type 1. J Virol. 1995 May; 69(5):3216-9.
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Engelman A, Englund G, Orenstein JM, Martin MA, Craigie R. Multiple effects of mutations in human immunodeficiency virus type 1 integrase on viral replication. J Virol. 1995 May; 69(5):2729-36.
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Dyda F, Hickman AB, Jenkins TM, Engelman A, Craigie R, Davies DR. Crystal structure of the catalytic domain of HIV-1 integrase: similarity to other polynucleotidyl transferases. Science. 1994 Dec 23; 266(5193):1981-6.
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Vicenzi E, Dimitrov DS, Engelman A, Migone TS, Purcell DF, Leonard J, Englund G, Martin MA. An integration-defective U5 deletion mutant of human immunodeficiency virus type 1 reverts by eliminating additional long terminal repeat sequences. J Virol. 1994 Dec; 68(12):7879-90.
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Hickman AB, Palmer I, Engelman A, Craigie R, Wingfield P. Biophysical and enzymatic properties of the catalytic domain of HIV-1 integrase. J Biol Chem. 1994 Nov 18; 269(46):29279-87.
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Engelman A. Most of the avian genome appears available for retroviral DNA integration. Bioessays. 1994 Nov; 16(11):797-9.
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Engelman A, Hickman AB, Craigie R. The core and carboxyl-terminal domains of the integrase protein of human immunodeficiency virus type 1 each contribute to nonspecific DNA binding. J Virol. 1994 Sep; 68(9):5911-7.
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Mazumder A, Engelman A, Craigie R, Fesen M, Pommier Y. Intermolecular disintegration and intramolecular strand transfer activities of wild-type and mutant HIV-1 integrase. Nucleic Acids Res. 1994 Mar 25; 22(6):1037-43.
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Engelman A, Bushman FD, Craigie R. Identification of discrete functional domains of HIV-1 integrase and their organization within an active multimeric complex. EMBO J. 1993 Aug; 12(8):3269-75.
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Bushman FD, Engelman A, Palmer I, Wingfield P, Craigie R. Domains of the integrase protein of human immunodeficiency virus type 1 responsible for polynucleotidyl transfer and zinc binding. Proc Natl Acad Sci U S A. 1993 Apr 15; 90(8):3428-32.
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Engelman A, Craigie R. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J Virol. 1992 Nov; 66(11):6361-9.
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Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell. 1991 Dec 20; 67(6):1211-21.
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Craigie R, Mizuuchi K, Bushman FD, Engelman A. A rapid in vitro assay for HIV DNA integration. Nucleic Acids Res. 1991 May 25; 19(10):2729-34.
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Engelman A, Rosenberg N. Temperature-sensitive mutants of Abelson murine leukemia virus deficient in protein tyrosine kinase activity. J Virol. 1990 Sep; 64(9):4242-51.
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Engelman A, Rosenberg N. bcr/abl and src but not myc and ras replace v-abl in lymphoid transformation. Mol Cell Biol. 1990 Aug; 10(8):4365-9.
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Engelman A, Rosenberg N. The Abelson protein is required for initiation and maintenance for transformation in murine pre-B cells. Curr Top Microbiol Immunol. 1988; 141:310-5.
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Engelman A, Rosenberg N. Isolation of temperature-sensitive Abelson virus mutants by site-directed mutagenesis. Proc Natl Acad Sci U S A. 1987 Nov; 84(22):8021-5.
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