Photo of Alan N. Engelman,  PhD

Alan N. Engelman, PhD

Dana-Farber Cancer Institute

Dana-Farber Cancer Institute
Phone: (617) 632-4361
Fax: (617) 632-4338


alan_engelman@dfci.harvard.edu

Alan N. Engelman, PhD

Dana-Farber Cancer Institute

EDUCATIONAL TITLES

  • Professor, Medicine, Harvard Medical School
  • Professor of Medicine, Cancer Immunology and Virology, Dana-Farber Cancer Institute

DF/HCC PROGRAM AFFILIATION

Research Abstract

Dr. Engelman focuses 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 Dr. Engelman's research borrows form 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, and Dr. Engelman`s research 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. Because X-ray crystal structures pinpointed the LEDGF binding face distal from the integrase active site, small molecule inhibitors of the LEDGF-integrase interaction should afford a novel way to block HIV-1 replication in cells.

Publications

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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 Specific 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. PubMed
  • 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. PubMed
  • 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; 530:358-61. PubMed
  • Serrao E, Cherepanov P, Engelman AN. Amplification, Next-generation Sequencing, and Genomic DNA Mapping of Retroviral Integration Sites. 2016. PubMed
  • Nuñez JK, Harrington LB, Kranzusch PJ, Engelman AN, Doudna JA. Foreign DNA capture during CRISPR-Cas adaptive immunity. Nature 2015; 527:535-8. PubMed
  • Serrao E, Engelman AN. Sites of retroviral DNA integration: From basic research to clinical applications. Crit Rev Biochem Mol Biol 2015. PubMed
  • 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; 523:366-9. PubMed
  • Nuñez JK, Lee AS, Engelman A, Doudna JA. Integrase-mediated spacer acquisition during CRISPR-Cas adaptive immunity. Nature 2015; 519:193-8. PubMed
  • Serrao E, Ballandras-Colas A, Cherepanov P, Maertens GN, Engelman AN. Key determinants of target DNA recognition by retroviral intasomes. Retrovirology 2015; 12:39. PubMed
  • Li M, Jurado KA, Lin S, Engelman A, Craigie R. Engineered hyperactive integrase for concerted HIV-1 DNA integration. PLoS ONE 2014; 9:e105078. PubMed
  • Kvaratskhelia M, Sharma A, Larue RC, Serrao E, Engelman A. Molecular mechanisms of retroviral integration site selection. Nucleic Acids Res 2014; 42:10209-25. PubMed
  • Ballandras-Colas A, Naraharisetty H, Li X, Serrao E, Engelman A. Biochemical characterization of novel retroviral integrase proteins. PLoS ONE 2013; 8:e76638. PubMed
  • 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. PubMed
  • Engelman A, Cherepanov P. The structural biology of HIV-1: mechanistic and therapeutic insights. Nat Rev Microbiol 2012; 10:279-90. PubMed
  • 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; 86:3861-79. PubMed
  • 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; 86:4708-14. PubMed
  • 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; 85:7818-27. PubMed
  • 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. PubMed
  • 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; 108:9244-9. PubMed
  • Koh Y, Matreyek KA, Engelman A. Differential sensitivities of retroviruses to integrase strand transfer inhibitors. J Virol 2011; 85:3677-82. PubMed
  • Li X, Krishnan L, Cherepanov P, Engelman A. Structural biology of retroviral DNA integration. Virology 2011; 411:194-205. PubMed
  • 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 2010; 55:42-9. PubMed
  • 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; 107:15910-5. PubMed
  • 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; 7:221-233. PubMed
  • Hare S, Gupta SS, Valkov E, Engelman A, Cherepanov P. Retroviral intasome assembly and inhibition of DNA strand transfer. Nature 2010; 464:232-6. PubMed
  • 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; 107:3135-40. PubMed
  • 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 2009; 84:397-406. PubMed
  • 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 2009; 285:541-54. PubMed
  • Engelman A, Oztop I, Vandegraaff N, Raghavendra NK. Quantitative analysis of HIV-1 preintegration complexes. Methods 2009; 47:283-90. PubMed
  • Engelman A. Mechanistic and pharmacological analyses of HIV-1 integration. Methods 2009; 47:225-8. PubMed
  • 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; 5:e1000327. PubMed
  • Engelman A. Isolation and analysis of HIV-1 preintegration complexes. Methods Mol Biol 2008; 485:135-49. PubMed
  • 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; 5:e1000259. PubMed
  • 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; 6:94. PubMed
  • 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; 82:11555-67. PubMed
  • 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; 283:31802-12. PubMed
  • Engelman A, Cherepanov P. The lentiviral integrase binding protein LEDGF/p75 and HIV-1 replication. PLoS Pathog 2008; 4:e1000046. PubMed
  • 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; 36:1237-46. PubMed
  • 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 2007; 283:5632-41. PubMed
  • 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; 319:921-6. PubMed
  • 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; 21:1767-78. PubMed
  • 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; 81:7099-110. PubMed
  • Engelman A. AIDS/HIV. A reversal of fortune in HIV-1 integration. Science 2007; 316:1855-7. PubMed
  • 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; 81:4381-5. PubMed
  • 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; 360:1-5. PubMed
  • 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 2006; 357:79-90. PubMed
  • Vandegraaff N, Engelman A. Molecular mechanisms of HIV integration and therapeutic intervention. Expert Rev Mol Med 2007; 9:1-19. PubMed
  • 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 2006; 81:166-72. PubMed
  • 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; 80:9754-60. PubMed
  • 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; 351:404-19. PubMed
  • Maertens GN, Cherepanov P, Engelman A. Transcriptional co-activator p75 binds and tethers the Myc-interacting protein JPO2 to chromatin. J Cell Sci 2006; 119:2563-71. PubMed
  • 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; 103:7454-9. PubMed
  • 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; 34:1653-75. PubMed
  • Byers KB, Engelman A, Fontes B. General guidelines for experimenting with HIV. Curr Protoc Immunol 2008; Chapter 12:Unit 12.1. PubMed
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