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

Powered by Harvard Catalyst
  • 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
  • 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
  • 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
  • Ballandras-Colas A, Naraharisetty H, Li X, Serrao E, Engelman A. Biochemical characterization of novel retroviral integrase proteins. PLoS ONE 2013; 8:e76638. 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
  • 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. A 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
  • 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
  • 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
  • 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 The H, Saib A. Impairment of human immunodeficiency virus type-1 integrase SUMOylation correlates with an early replication defect. J Biol Chem 2011. 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. Mechanistic and pharmacological analyses of HIV-1 integration. Methods 2009; 47:225-8. PubMed
  • Engelman A, Oztop I, Vandegraaff N, Raghavendra NK. Quantitative analysis of HIV-1 preintegration complexes. Methods 2009; 47:283-90. 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
  • 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
  • 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
  • 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
  • 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 2005; 346:415-26. 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
  • 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; 102:17308-13. PubMed
  • 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; 79:12584-91. PubMed
  • 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; 79:10356-68. PubMed
  • 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; 12:526-32. PubMed
  • Lu R, Lim. Genetic analyses of DNA-binding mutants in the catalytic core domain of human immunodeficiency virus type 1 integrase. J Virol 2005; 79:2493-505. PubMed
  • Engelman A. The ups and downs of gene expression and retroviral DNA integration. Proc Natl Acad Sci U S A 2005; 102:1275-6. PubMed
  • Devroe E, Silver PA, Engelman A. HIV-1 incorporates and proteolytically processes human NDR1 and NDR2 serine-threonine kinases. Virology 2004; 331:181-9. PubMed
  • Lu R, Lim. 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; 78:12735-46. PubMed
  • 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; 279:48883-92. PubMed
  • Turlure F, Devroe E, Silver PA, Engelman A. Human cell proteins and human immunodeficiency virus DNA integration. Front Biosci 2004; 9:3187-208. PubMed
  • 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; 279:33421-9. PubMed
  • Byers KB, Engelman A, Fontes B. General guidelines for experimenting with HIV. Curr Protoc Immunol 2008; Chapter 12:Unit 12.1. PubMed
  • 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 2003; 78:658-68. PubMed
  • Devroe E, Engelman A, Silver PA. Intracellular transport of human immunodeficiency virus type 1 integrase. J Cell Sci 2003; 116:4401-8. PubMed
  • Lin CW, Engelman A. The barrier-to-autointegration factor is a component of functional human immunodeficiency virus type 1 preintegration complexes. J Virol 2003; 77:5030-6. PubMed
  • Engelman A. The roles of cellular factors in retroviral integration. Curr Top Microbiol Immunol 2003; 281:209-38. PubMed
  • Lim. Wild-type levels of nuclear localization and human immunodeficiency virus type 1 replication in the absence of the central DNA flap. J Virol 2002; 76:12078-86. PubMed
  • Lim. 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; 76:10598-607. PubMed
  • 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; 21:6758-67. PubMed
  • 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; 75:7944-55. PubMed
  • 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; 275:39671-7. PubMed
  • 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; 74:8188-93. PubMed
  • 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; 73:9011-20. PubMed
  • 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; 274:17358-64. PubMed
  • Engelman A. In vivo analysis of retroviral integrase structure and function. Adv Virus Res 1999; 52:411-26. PubMed
  • 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; 95:15270-4. PubMed
  • 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 1998; 16:6849-59. PubMed
  • 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; 71:8124-32. PubMed
  • 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; 71:3507-14. PubMed
  • 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; 70:8277-84. PubMed
  • Engelman A. Biochemical characterization of recombinant equine infectious anemia virus integrase. Protein Expr Purif 1996; 8:299-304. PubMed
  • 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; 271:7712-8. PubMed
  • Engelman A, Craigie R. Efficient magnesium-dependent human immunodeficiency virus type 1 integrase activity. J Virol 1995; 69:5908-11. PubMed
  • 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; 34:9826-33. PubMed
  • 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; 69:2729-36. PubMed
  • Englund G, Theodore TS, Freed EO, Engleman A, Martin MA. Integration is required for productive infection of monocyte-derived macrophages by human immunodeficiency virus type 1. J Virol 1995; 69:3216-9. PubMed
  • 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; 266:1981-6. PubMed
  • 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; 68:7879-90. PubMed
  • 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; 269:29279-87. PubMed
  • Engelman A. Most of the avian genome appears available for retroviral DNA integration. Bioessays 1994; 16:797-9. PubMed
  • 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; 68:5911-7. PubMed
  • 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; 22:1037-43. PubMed
  • 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; 12:3269-75. PubMed
  • 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; 90:3428-32. PubMed
  • Engelman A, Craigie R. Identification of conserved amino acid residues critical for human immunodeficiency virus type 1 integrase function in vitro. J Virol 1992; 66:6361-9. PubMed
  • Engelman A, Mizuuchi K, Craigie R. HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell 1991; 67:1211-21. PubMed
  • Craigie R, Mizuuchi K, Bushman FD, Engelman A. A rapid in vitro assay for HIV DNA integration. Nucleic Acids Res 1991; 19:2729-34. PubMed
  • Engelman A, Rosenberg N. Temperature-sensitive mutants of Abelson murine leukemia virus deficient in protein tyrosine kinase activity. J Virol 1990; 64:4242-51. PubMed
  • Engelman A, Rosenberg N. bcr/abl and src but not myc and ras replace v-abl in lymphoid transformation. Mol Cell Biol 1990; 10:4365-9. PubMed
  • Engelman A, Rosenberg N. The Abelson protein is required for initiation and maintenance for transformation in murine pre-B cells. Curr Top Microbiol Immunol 1987; 141:310-5. PubMed
  • Engelman A, Rosenberg N. Isolation of temperature-sensitive Abelson virus mutants by site-directed mutagenesis. Proc Natl Acad Sci U S A 1987; 84:8021-5. PubMed
Hide