Structural Basis for Inhibitor-Induced Aggregation of HIV Integrase
Open accessAbstract
The allosteric inhibitors of integrase (termed ALLINIs) interfere with HIV replication by binding to the viral-encoded integrase (IN) protein. Surprisingly, ALLINIs interfere not with DNA integration but with viral particle assembly late during HIV replication. To investigate the ALLINI inhibitory mechanism, we crystallized full-length HIV-1 IN bound to the ALLINI GSK1264 and determined the structure of the complex at 4.4 Å resolution. The structure shows GSK1264 buried between the IN C-terminal domain (CTD) and the catalytic core domain. In the crystal lattice, the interacting domains are contributed by two different dimers so that IN forms an open polymer mediated by inhibitor-bridged contacts; the N-terminal domains do not participate and are structurally disordered. Engineered amino acid substitutions at the inhibitor interface blocked ALLINI-induced multimerization. HIV escape mutants with reduced sensitivity to ALLINIs commonly altered amino acids at or near the inhibitor-bound interface, and these substitutions also diminished IN multimerization. We propose that ALLINIs inhibit particle assembly by stimulating inappropriate polymerization of IN via interactions between the catalytic core domain and the CTD and that understanding the interface involved offers new routes to inhibitor optimization.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
ALLINI resistance maps to the integrase CCD dimer interface near the LEDGF/p75 binding site.
“Resistance to ALLINIs maps to the IN CCD dimer interface in the vicinity of the LEDGF/p75 binding site171,173,179,182,188.”
From Structure and function of retroviral integrase (2022) · cites this paper as [179]
The Introduction places the LEDGF/p75 binding site at the integrase catalytic core domain (CCD) dimer interface, and the Discussion identifies some ALLINI-resistance substitutions that likely interfere with inhibitor binding there. But the Discussion also identifies resistance substitutions affecting the CCD–CTD interaction or residing in the N-terminal domain, so the claim overstates where resistance maps. Our copy provides section labels but no page numbers. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe common biochemical consequence of ALLINI binding is aberrant HIV-1 integrase hyper-multimerization.
“The common biochemical consequence of ALLINI binding is aberrant HIV-1 IN hyper-multimerization140,142,174–181.”
From Structure and function of retroviral integrase (2022) · cites this paper as [179]
ALLINIs do not act by inhibiting integration.
“Counterintuitively, the underlying mode of ALLINI action is not via inhibition of integration140,142,174–177,179–181.”
From Structure and function of retroviral integrase (2022) · cites this paper as [179]
A co-crystal structure of full-length HIV-1 integrase with GSK1264 showed that binding at the CCD dimer interface creates a novel CTD interface, leading to linear integrase polymers.
“A co-crystal structure of full-length HIV-1 IN with GSK1264 revealed that binding of this ALLINI at the CCD dimer interface contributes to a novel interface for the CTD, leading to formation of linear IN polymers (Fig. 6D)179.”
From Structure and function of retroviral integrase (2022) · cites this paper as [179]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Regression shrinkage and selection via the lasso
Tibshirani, R. (1996) · Journal of the Royal Statistical Society Series B: Statistical Methodology · doi:10.1111/j.2517-6161.1996.tb02080.x · Cited by 51,482 · see citing works
Features and development of Coot
Emsley, P., Lohkamp, B., Scott, W. G., & Cowtan, K. D. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910007493 · Cited by 27,510 · see citing works
<i>PHENIX</i> : a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkóczi, G., Chen, V. B., Davis, I. W., Echols, N., Headd, J. J., Hung, L.-W., Kapral, G. J., Grosse-Kunstleve, R. W., et al. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909052925 · Cited by 23,716 · see citing works
<i>Phaser</i> crystallographic software
McCoy, A. J., Grosse-Kunstleve, R. W., Adams, P. D., Winn, M. D., Storoni, L. C., & Read, R. J. (2007) · Journal of Applied Crystallography · doi:10.1107/s0021889807021206 · Cited by 20,612 · see citing works
Kabsch, W. (2010) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444909047337 · Cited by 16,463 · see citing works
Crystallography & NMR System: A New Software Suite for Macromolecular Structure Determination
Brünger, A. T., Adams, P. D., Clore, G. M., DeLano, W. L., Gros, P., Grosse‐Kunstleve, R. W., Jiang, J., Kuszewski, J. J., Nilges, M., Pannu, N., et al. (1998) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444998003254 · Cited by 15,720 · see citing works
PHENIX: a comprehensive Python-based system for macromolecular structure solution
Adams, P. D., Afonine, P. V., Bunkòczi, G., Chen, V. B., Davis, I., Echols, N., Headd, J. J., Hung, L., Kapral, G. J., Grosse‐Kunstleve, R. W., et al. (2012) · International Tables for Crystallography · doi:10.1107/97809553602060000865 · Cited by 7,334 · see citing works
LigPlot+: Multiple Ligand-Protein Interaction Diagrams for Drug Discovery
Laskowski, R., & Swindells, M. (2011) · Journal of Chemical Information and Modeling · doi:10.1021/ci200227u · Cited by 6,159 · see citing works
Schuck, P. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76713-0 · Cited by 3,868 · see citing works
HIV-1 Integration in the Human Genome Favors Active Genes and Local Hotspots
Schröder, A. R. W., Shinn, P., Chen, H., Berry, C., Ecker, J. R., & Bushman, F. (2002) · Cell · doi:10.1016/s0092-8674(02)00864-4 · Cited by 1,832 · see citing works
Self-citationSolving structures of protein complexes by molecular replacement with Phaser
McCoy, A. J. (2006) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444906045975 · Cited by 1,605 · see citing works
Version 1.2 of the Crystallography and NMR system
Brünger, A. T. (2007) · Nature Protocols · doi:10.1038/nprot.2007.406 · Cited by 1,335 · see citing works
HIV-1 Antiretroviral Drug TherapyPreprint
Arts, E. J., & Hazuda, D. J. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a007161 · Cited by 856 · see citing works
Strong, M., Sawaya, M. R., Wang, S., Phillips, M. L., Cascio, D., & Eisenberg, D. S. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0602606103 · Cited by 701 · see citing works
Retroviral intasome assembly and inhibition of DNA strand transfer
Hare, S., Gupta, S. S., Valkov, E., Engelman, A., & Cherepanov, P. (2010) · Nature · doi:10.1038/nature08784 · Cited by 678 · see citing works
A role for LEDGF/p75 in targeting HIV DNA integration
Ciuffi, A., Llano, M., Poeschla, E., Hoffmann, C., Leipzig, J., Shinn, P., Ecker, J. R., & Bushman, F. (2005) · Nature Medicine · doi:10.1038/nm1329 · Cited by 658 · see citing works
Self-citationMolecular Mechanism of Action of Microtubule-Stabilizing Anticancer Agents
Prota, A. E., Bargsten, K., Zurwerra, D., Field, J. J., Díaz, J. F., Altmann, K., & Steinmetz, M. O. (2013) · Science · doi:10.1126/science.1230582 · Cited by 494 · see citing works
Christ, F., Voet, A., Marchand, A., Nicolet, S., Desimmie, B. A., Marchand, D., Bardiot, D., Van der Veken, N. J., Van Remoortel, B., Strelkov, S. V., et al. (2010) · Nature Chemical Biology · doi:10.1038/nchembio.370 · Cited by 479 · see citing works
Shun, M.-C., Raghavendra, N. K., Vandegraaff, N., Daigle, J. E., Hughes, S., Kellam, P., Cherepanov, P., & Engelman, A. (2007) · Genes & Development · doi:10.1101/gad.1565107 · Cited by 467 · see citing works
The structural biology of HIV-1: mechanistic and therapeutic insights
Engelman, A., & Cherepanov, P. (2012) · Nature Reviews Microbiology · doi:10.1038/nrmicro2747 · Cited by 426 · see citing works
Bushman, F. D., & Craigie, R. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.4.1339 · Cited by 410 · see citing works
Self-citationChen, J. C.-H., Krucinski, J., Miercke, L. J. W., Finer-Moore, J. S., Tang, A. H., Leavitt, A. D., & Stroud, R. M. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.150220297 · Cited by 404 · see citing works
Three new structures of the core domain of HIV-1 integrase: An active site that binds magnesium
Goldgur, Y., Dyda, F., Hickman, A. B., Jenkins, T. M., Craigie, R., & Davies, D. R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.16.9150 · Cited by 380 · see citing works
Retroviral DNA integration directed by HIV integration protein in vitro
Bushman, F. D., Fujiwara, T., & Craigie, R. (1990) · Science · doi:10.1126/science.2171144 · Cited by 338 · see citing works
Self-citationWang, J.-Y., Ling, H., Yang, W., & Craigie, R. (2001) · The EMBO Journal · doi:10.1093/emboj/20.24.7333 · Cited by 332 · see citing works
Craigie, R., & Bushman, F. D. (2012) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a006890 · Cited by 327 · see citing works
Self-citationA Soluble Active Mutant of HIV-1 Integrase
Jenkins, T. M., Engelman, A., Ghirlando, R., & Craigie, R. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.13.7712 · Cited by 271 · see citing works
Jurado, K. A., Wang, H., Slaughter, A., Feng, L., Kessl, J. J., Koh, Y., Wang, W., Ballandras-Colas, A., Patel, P. A., Fuchs, J. R., et al. (2013) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1300703110 · Cited by 203 · see citing works
Discovery of BI 224436, a Noncatalytic Site Integrase Inhibitor (NCINI) of HIV-1
Fader, L. D., Malenfant, E., Parisien, M., Carson, R., Bilodeau, F., Landry, S., Pesant, M., Brochu, C., Morin, S., Chabot, C., et al. (2014) · ACS Medicinal Chemistry Letters · doi:10.1021/ml500002n · Cited by 178 · see citing works
Christ, F., Shaw, S. M., Demeulemeester, J., Desimmie, B. A., Marchand, A., Butler, S., Smets, W. J., Chaltin, P., Westby, M., Debyser, Z., et al. (2012) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00717-12 · Cited by 176 · see citing works
New Class of HIV-1 Integrase (IN) Inhibitors with a Dual Mode of Action
Tsiang, M., Jones, G. S., Niedziela-Majka, A., Kan, E., Lansdon, E. B., Huang, W., Hung, M., Samuel, D., Novikov, N., Xu, Y., et al. (2012) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.347534 · Cited by 167 · see citing works
Hare, S., Shun, M.-C., Gupta, S. S., Valkov, E., Engelman, A., & Cherepanov, P. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000259 · Cited by 166 · see citing works
Oligomeric States of the HIV-1 Integrase As Measured by Time-Resolved Fluorescence Anisotropy
Deprez, E., Tauc, P., Leh, H., Mouscadet, J. F., Auclair, C., & Brochon, J. (2000) · Biochemistry · doi:10.1021/bi000397j · Cited by 134 · see citing works
Gao, K., Butler, S., & Bushman, F. (2001) · EMBO Journal · doi:10.1093/emboj/20.13.3565 · Cited by 133 · see citing works
Self-citationLe Rouzic, E., Bonnard, D., Chasset, S., Bruneau, J.-M., Chevreuil, F., Le Strat, F., Nguyen, J., Beauvoir, R., Amadori, C., Brias, J., et al. (2013) · Retrovirology · doi:10.1186/1742-4690-10-144 · Cited by 127 · see citing works
Balakrishnan, M., Yant, S. R., Tsai, L., O’Sullivan, C., Bam, R. A., Tsai, A., Niedziela-Majka, A., Stray, K. M., Sakowicz, R., & Cihlar, T. (2013) · PLoS ONE · doi:10.1371/journal.pone.0074163 · Cited by 126 · see citing works
A New Class of Multimerization Selective Inhibitors of HIV-1 Integrase
Sharma, A., Slaughter, A., Jena, N., Feng, L., Kessl, J. J., Fadel, H. J., Malani, N., Male, F., Wu, L., Poeschla, E., et al. (2014) · PLoS Pathogens · doi:10.1371/journal.ppat.1004171 · Cited by 124 · see citing works
Self-citationStructural Basis for Functional Tetramerization of Lentiviral Integrase
Hare, S., Di Nunzio, F., Labeja, A., Wang, J., Engelman, A., & Cherepanov, P. (2009) · PLoS Pathogens · doi:10.1371/journal.ppat.1000515 · Cited by 122 · see citing works
Mitra, A., & Sept, D. (2008) · Biophysical Journal · doi:10.1529/biophysj.108.133884 · Cited by 119 · see citing works
The LEDGF/p75 integrase interaction, a novel target for anti-HIV therapy
Christ, F., & Debyser, Z. (2012) · Virology · doi:10.1016/j.virol.2012.09.033 · Cited by 109 · see citing works
Chen, Z., Yan, Y., Munshi, S. K., Li, Y., Zugay-Murphy, J., Xu, B., Witmer, M. V., Felock, P. J., Wolfe, A. L., Sardana, V. V., et al. (2000) · Journal of Molecular Biology · doi:10.1006/jmbi.1999.3451 · Cited by 102 · see citing works
Feng, L., Sharma, A., Slaughter, A., Jena, N., Koh, Y., Shkriabai, N., Larue, R. C., Patel, P. A., Mitsuya, H., Kessl, J., et al. (2013) · Journal of Biological Chemistry · doi:10.1074/jbc.m112.443390 · Cited by 99 · see citing works
Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor
Fenwick, C., Amad, M., Bailey, M. D., Bethell, R., Bös, M., Bonneau, P., Cordingley, M., Coulombe, R., Duan, J., Edwards, P., et al. (2014) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.02719-13 · Cited by 99 · see citing works
Fontana, J., Jurado, K. A., Cheng, N., Ly, N. L., Fuchs, J. R., Gorelick, R. J., Engelman, A. N., & Steven, A. C. (2015) · Journal of Virology · doi:10.1128/jvi.01522-15 · Cited by 96 · see citing works
Molteni, V., Greenwald, J., Rhodes, D., Hwang, Y. S., Kwiatkowski, W., Bushman, F. D., Siegel, J. S., & Choe, S. (2001) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444901001652 · Cited by 89 · see citing works
Self-citationAllosteric Inhibition of Human Immunodeficiency Virus Integrase
Gupta, K., Brady, T., Dyer, B. M., Malani, N., Hwang, Y., Male, F., Nolte, R. T., Wang, L., Velthuisen, E., Jeffrey, J., et al. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.551119 · Cited by 81 · see citing works
Self-citationStructure-based mutagenesis of the catalytic domain of human immunodeficiency virus type 1 integrase
Engelman, A., Liu, Y., Chen, H., Farzan, M., & Dyda, F. (1997) · Journal of Virology · doi:10.1128/jvi.71.5.3507-3514.1997 · Cited by 74 · see citing works
Ciuffi, A., Diamond, T. L., Hwang, Y. S., Marshall, H. M., & Bushman, F. D. (2006) · Human Gene Therapy · doi:10.1089/hum.2006.17.960 · Cited by 62 · see citing works
Self-citationHIV integrase as a target for antiretroviral therapy
Hazuda, D. J. (2012) · Current Opinion in HIV and AIDS · doi:10.1097/coh.0b013e3283567309 · Cited by 61 · see citing works
Nishitsuji, H., Hayashi, T., Takahashi, T., Miyano, M., Kannagi, M., & Masuda, T. (2009) · PLoS ONE · doi:10.1371/journal.pone.0007825 · Cited by 38 · see citing works
Slaughter, A., Jurado, K. A., Deng, N., Feng, L., Kessl, J. J., Shkriabai, N., Larue, R. C., Fadel, H. J., Patel, P. A., Jena, N., et al. (2014) · Retrovirology · doi:10.1186/s12977-014-0100-1 · Cited by 38 · see citing works
Alian, A., Griner, S. L., Chiang, V., Tsiang, M., Jones, G. S., Birkuš, G., Geleziunas, R., Leavitt, A. D., & Stroud, R. M. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0811919106 · Cited by 36 · see citing works
Improving the Accuracy of Macromolecular Structure Refinement at 7 Å Resolution
Brünger, A. T., Adams, P. D., Fromme, P., Fromme, R., Levitt, M., & Schroeder, G. F. (2012) · Structure · doi:10.1016/j.str.2012.04.020 · Cited by 36 · see citing works
Shkriabai, N., Dharmarajan, V., Slaughter, A., Kessl, J. J., Larue, R. C., Feng, L., Fuchs, J. R., Griffin, P. R., & Kvaratskhelia, M. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.589572 · Cited by 30 · see citing works
Deformable elastic network refinement for low-resolution macromolecular crystallography
Schroeder, G. F., Levitt, M., & Brünger, A. T. (2014) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s1399004714016496 · Cited by 30 · see citing works
Isolation and Characterization of an Oligomerization-Negative Mutant of HIV-1 Integrase
Kalpana, G. V., Reicin, A. S., Cheng, G. S. W., Sorin, M., Paik, S., & Goff, S. P. (1999) · Virology · doi:10.1006/viro.1999.9767 · Cited by 27 · see citing works
Diamond, T. L., & Bushman, F. D. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkl862 · Cited by 27 · see citing works
Self-citationBrünger, A. T., Das, D., Deacon, A. M., Grant, J. C., Terwilliger, T. C., Read, R. J., Adams, P. D., Levitt, M., & Schroeder, G. F. (2012) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s090744491104978x · Cited by 26 · see citing works
Inoue, M., Hoxie, J. A., Reddy, M. V., Srinivasan, A., & Reddy, E. P. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.6.2278 · Cited by 26 · see citing works
Structural Properties of HIV Integrase·Lens Epithelium-derived Growth Factor Oligomers
Gupta, K., Diamond, T. L., Hwang, Y. S., Bushman, F. D., & Duyne, G. D. V. (2010) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.114413 · Cited by 24 · see citing works
Self-citationNomura, Y., Masuda, T., & Kawai, G. (2006) · The Journal of Biochemistry · doi:10.1093/jb/mvj085 · Cited by 14 · see citing works
Flagged first, then by citations
1 of the 62 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Structure and function of retroviral integrase
Maertens, G. N., Engelman, A. N., & Cherepanov, P. (2022) · Nature Reviews Microbiology · doi:10.1038/s41579-021-00586-9 · Cited by 124 · see citing works
HIV-1 Maturation: Lessons Learned from Inhibitors
Kleinpeter, A. B., & Freed, E. O. (2020) · Viruses · doi:10.3390/v12090940 · Cited by 95 · see citing works
Cellular and molecular mechanisms of HIV-1 integration targeting
Engelman, A., & Singh, P. K. (2018) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-018-2772-5 · Cited by 89 · see citing works
Multifaceted HIV integrase functionalities and therapeutic strategies for their inhibition
Engelman, A. (2019) · Journal of Biological Chemistry · doi:10.1074/jbc.rev119.006901 · Cited by 78 · see citing works
Integrase-RNA interactions underscore the critical role of integrase in HIV-1 virion morphogenesis
Elliott, J. L., Eschbach, J. E., Koneru, P. C., Li, W., Puray-Chavez, M., Townsend, D., Lawson, D. Q., Engelman, A. N., Kvaratskhelia, M., & Kutluay, S. B. (2020) · eLife · doi:10.7554/elife.54311 · Cited by 59 · see citing works
Engelman, A., & Cherepanov, P. (2017) · Current Opinion in Structural Biology · doi:10.1016/j.sbi.2017.04.005 · Cited by 56 · see citing works
HIV-1 integrase tetramers are the antiviral target of pyridine-based allosteric integrase inhibitors
Koneru, P. C., Francis, A. C., Deng, N., Rebensburg, S. V., Hoyte, A. C., Lindenberger, J., Adu-Ampratwum, D., Larue, R. C., Wempe, M. F., Engelman, A. N., et al. (2019) · eLife · doi:10.7554/elife.46344 · Cited by 49 · see citing works
Going beyond Integration: The Emerging Role of HIV-1 Integrase in Virion Morphogenesis
Elliott, J. L., & Kutluay, S. B. (2020) · Viruses · doi:10.3390/v12091005 · Cited by 46 · see citing works
Bonnard, D., Le Rouzic, E., Eiler, S., Amadori, C., Orlov, I., Bruneau, J.-M., Brias, J., Barbion, J., Chevreuil, F., Spehner, D., et al. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.816793 · Cited by 42 · see citing works
Recent Advances in the Discovery of Small-Molecule Inhibitors of HIV-1 Integrase
Choi, E., Mallareddy, J. R., Lu, D., & Kolluru, S. (2018) · Future Science OA · doi:10.4155/fsoa-2018-0060 · Cited by 41 · see citing works
Augmenting Hit Identification by Virtual Screening Techniques in Small Molecule Drug Discovery
Yan, X. C., Sanders, J. M., Gao, Y.-D., Tudor, M., Haidle, A. M., Klein, D. J., Converso, A., Lesburg, C. A., Zang, Y., & Wood, H. B. (2020) · Journal of Chemical Information and Modeling · doi:10.1021/acs.jcim.0c00113 · Cited by 41 · see citing works
Structural basis of host protein hijacking in human T-cell leukemia virus integration
Bhatt, V., Shi, K., Salamango, D. J., Moeller, N. H., Pandey, K. K., Bera, S., Bohl, H. O., Kurniawan, F., Orellana, K., Zhang, W., et al. (2020) · Nature Communications · doi:10.1038/s41467-020-16963-6 · Cited by 39 · see citing works
Maehigashi, T., Ahn, S., Kim, U.-I., Lindenberger, J. J., Oo, A., Koneru, P. C., Mahboubi, B., Engelman, A., Kvaratskhelia, M., Kim, K., et al. (2021) · PLoS Pathogens · doi:10.1371/journal.ppat.1009671 · Cited by 38 · see citing works
Capsid–host interactions for HIV-1 ingress
Jang, S., & Engelman, A. (2023) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00048-22 · Cited by 37 · see citing works
Madison, M. K., Lawson, D. Q., Elliott, J. L., Ozantürk, A. N., Koneru, P. C., Townsend, D., Errando, M., Kvaratskhelia, M., & Kutluay, S. B. (2017) · Journal of Virology · doi:10.1128/jvi.00821-17 · Cited by 34 · see citing works
Multimodal Functionalities of HIV-1 Integrase
Engelman, A., & Kvaratskhelia, M. (2022) · Viruses · doi:10.3390/v14050926 · Cited by 33 · see citing works
Guo, L., Meanwell, N. A., Krystal, M., Langley, D. R., Naidu, B. N., Sivaprakasam, P., Lewis, H. A., Kish, K., Khan, J., Ng, A., et al. (2020) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.9b01681 · Cited by 32 · see citing works
Synthesis and Evaluation of Aryl Quinolines as HIV-1 Integrase Multimerization Inhibitors
Jentsch, N. G., Hart, A. P., Hume, J. D., Sun, J., McNeely, K. A., Lama, C., Pigza, J. A., Donahue, M. G., & Kessl, J. J. (2018) · ACS Medicinal Chemistry Letters · doi:10.1021/acsmedchemlett.8b00269 · Cited by 31 · see citing works
Hoyte, A. C., Jamin, A. V., Koneru, P. C., Kobe, M. J., Larue, R. C., Fuchs, J. R., Engelman, A. N., & Kvaratskhelia, M. (2017) · Journal of Biological Chemistry · doi:10.1074/jbc.m117.816645 · Cited by 30 · see citing works
Exploring the Free-Energy Landscape and Thermodynamics of Protein-Protein Association
Tse, C., Wickstrom, L., Kvaratskhelia, M., Gallicchio, E., Levy, R. M., & Deng, N. (2020) · Biophysical Journal · doi:10.1016/j.bpj.2020.08.005 · Cited by 30 · see citing works
Gupta, K., Allen, A., Giraldo, C., Eilers, G., Sharp, R., Hwang, Y., Murali, H., Cruz, K., Janmey, P., Bushman, F., et al. (2021) · Structure · doi:10.1016/j.str.2020.12.001 · Cited by 19 · see citing works
Self-citationThe Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function
Singer, M. R., Dinh, T., Levintov, L., Annamalai, A. S., Rey, J. S., Briganti, L., Cook, N., Pye, V. E., Taylor, I. A., Kim, K., et al. (2023) · mBio · doi:10.1128/mbio.03560-22 · Cited by 18 · see citing works
Exploring HIV-1 Maturation: A New Frontier in Antiviral Development
McGraw, A., Hillmer, G., Mehedincu, S. M., Hikichi, Y., Gagliardi, S., Narayan, K., Tibebe, H., Marquez, D., Bose, L. M., Keating, A., et al. (2024) · Viruses · doi:10.3390/v16091423 · Cited by 17 · see citing works
Retroviral integrase: Structure, mechanism, and inhibition
Passos, D. O., Li, M., Craigie, R., & Lyumkis, D. (2021) · The Enzymes · doi:10.1016/bs.enz.2021.06.007 · Cited by 18 · see citing works
Mugisha, C. S., Dinh, T., Kumar, A., Tenneti, K., Eschbach, J. E., Davis, K., Gifford, R. J., Kvaratskhelia, M., & Kutluay, S. B. (2022) · mBio · doi:10.1128/mbio.00431-22 · Cited by 16 · see citing works
Biological and Structural Analyses of New Potent Allosteric Inhibitors of HIV-1 Integrase
Bonnard, D., Rouzic, E. L., Singer, M. R., Yu, Z., Strat, F. L., Batisse, C., Batisse, J., Amadori, C., Chasset, S., Pye, V. E., et al. (2023) · Antimicrobial Agents and Chemotherapy · doi:10.1128/aac.00462-23 · Cited by 16 · see citing works
Ohata, Y., Tomonaga, M., Watanabe, Y., Tomura, K., Kimura, K., Akaki, T., Adachi, K., Kodama, E. N., Matsuzaki, Y., & Hayashi, H. (2022) · Journal of Virology · doi:10.1128/jvi.01843-21 · Cited by 14 · see citing works
Medicinal chemistry perspectives on the development of piperazine-containing HIV-1 inhibitors
Salubi, C. A., Abbo, H. S., Jahed, N., & Titinchi, S. J. J. (2024) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2024.117605 · Cited by 14 · see citing works
Burlein, C., Wang, C., Xu, M., Bhatt, T., Stahlhut, M. W., Ou, Y., Adam, G. C., Heath, J., Klein, D. J., Sanders, J. M., et al. (2017) · ACS Chemical Biology · doi:10.1021/acschembio.7b00550 · Cited by 14 · see citing works
CLIP-related methodologies and their application to retrovirology
Bieniasz, P. D., & Kutluay, S. B. (2018) · Retrovirology · doi:10.1186/s12977-018-0417-2 · Cited by 14 · see citing works
Optimized binding of substituted quinoline ALLINIs within the HIV-1 integrase oligomer
Sun, J., Patel, K., Hume, J. D., Pigza, J. A., Donahue, M. G., & Kessl, J. J. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100363 · Cited by 13 · see citing works
Imamichi, T., Bernbaum, J. G., Laverdure, S., Yang, J., Chen, Q., Highbarger, H., Hao, M., Sui, H., Dewar, R. L., Chang, W., et al. (2021) · Journal of Virology · doi:10.1128/jvi.01323-21 · Cited by 12 · see citing works
Singh, P., Li, W., Bedwell, G., Fadel, H., Poeschla, E., & Engelman, A. (2022) · Viruses · doi:10.3390/v14091883 · Cited by 13 · see citing works
Virus–Host Interactions in Retrovirus Integration
Engelman, A. N., & Maertens, G. N. (2018) · Retrovirus-Cell Interactions · doi:10.1016/b978-0-12-811185-7.00004-2 · Cited by 12 · see citing works
Li, M., Li, Z., Chen, X., Cui, Y., Engelman, A. N., & Craigie, R. (2024) · Viruses · doi:10.3390/v16071166 · Cited by 12 · see citing works
Eilers, G., Gupta, K., Allen, A., Montermoso, S., Murali, H., Sharp, R. B., Hwang, Y., Bushman, F. D., & Duyne, G. D. V. (2023) · PLoS Pathogens · doi:10.1371/journal.ppat.1011097 · Cited by 11 · see citing works
Self-citationThe Integrase: An Overview of a Key Player Enzyme in the Antiviral Scenario
Renzi, G., Carta, F., & Supuran, C. T. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241512187 · Cited by 11 · see citing works
Dinh, T., Tber, Z., Rey, J. S., Mengshetti, S., Annamalai, A. S., Haney, R., Briganti, L., Amblard, F., Fuchs, J. R., Cherepanov, P., et al. (2024) · mBio · doi:10.1128/mbio.00465-24 · Cited by 11 · see citing works
Wrangling Shape-Shifting Morpheeins to Tackle Disease and Approach Drug Discovery
Jaffe, E. K. (2020) · Frontiers in Molecular Biosciences · doi:10.3389/fmolb.2020.582966 · Cited by 11 · see citing works
Influence of the amino-terminal sequence on the structure and function of HIV integrase
Eilers, G., Gupta, K., Allen, A., Zhou, J. O., Hwang, Y., Cory, M., Bushman, F. D., & Duyne, G. D. V. (2020) · Retrovirology · doi:10.1186/s12977-020-00537-x · Cited by 11 · see citing works
Self-citationOptimizing the Multimerization Properties of Quinoline-Based Allosteric HIV-1 Integrase Inhibitors
Sun, J., & Kessl, J. J. (2024) · Viruses · doi:10.3390/v16020200 · Cited by 10 · see citing works
A Conformational Escape Reaction of HIV-1 against an Allosteric Integrase Inhibitor
Nakamura, T., Nakamura, T., Amano, M., Miyakawa, T., Yamagata, Y., Matsuoka, M., & Nakata, H. (2020) · Journal of Virology · doi:10.1128/jvi.00486-20 · Cited by 9 · see citing works
Multi-Substituted Quinolines as HIV-1 Integrase Allosteric Inhibitors
Dinh, L. P., Sun, J., Glenn, C. D., Patel, K., Pigza, J. A., Donahue, M. G., Yet, L., & Kessl, J. J. (2022) · Viruses · doi:10.3390/v14071466 · Cited by 9 · see citing works
Jing, T., Shan, Z., Dinh, T., Biswas, A., Jang, S., Greenwood, J., Li, M., Zhang, Z., Gray, G., Shin, H. J., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-64479-8 · Cited by 13 · see citing works
Brief Histories of Retroviral Integration Research and Associated International Conferences
Grandgenett, D. P., & Engelman, A. (2024) · Viruses · doi:10.3390/v16040604 · Cited by 7 · see citing works
Cyclic Hexapeptide Mimics of the LEDGF Integrase Recognition Loop in Complex with HIV‐1 Integrase
Northfield, S. E., Wielens, J., Headey, S. J., Williams‐Noonan, B. J., Mulcair, M. D., Scanlon, M. J., Parker, M. W., Thompson, P. E., & Chalmers, D. K. (2018) · ChemMedChem · doi:10.1002/cmdc.201800129 · Cited by 7 · see citing works
Musat, M., Nițulescu, G. M., Surleac, M. D., Tsatsakis, A. M., Spandidos, D. A., & Margina, D. M. (2019) · Molecular Medicine Reports · doi:10.3892/mmr.2019.10777 · Cited by 7 · see citing works
Sun, Q., Vijayan, R. S. K., Levy, R. M., & Deng, N. (2020) · Protein Science · doi:10.1002/pro.4004 · Cited by 7 · see citing works
Viral Protein Dimerization Quality Control: A Design Strategy for a Potential Viral Inhibitor
Du, S., Liu, X., Hu, X., & Zhan, P. (2024) · Journal of Medicinal Chemistry · doi:10.1021/acs.jmedchem.4c01540 · Cited by 5 · see citing works
Hutapea, H. M. L., Maladan, Y., & Widodo, N. (2018) · Heliyon · doi:10.1016/j.heliyon.2018.e00956 · Cited by 5 · see citing works
Thierry, E., Lebourgeois, S., Simon, F., Delelis, O., & Deprez, E. (2017) · Scientific Reports · doi:10.1038/s41598-017-14564-w · Cited by 5 · see citing works
Montermoso, S., Eilers, G., Allen, A., Sharp, R., Hwang, Y., Bushman, F. D., Gupta, K., & Duyne, G. D. V. (2025) · Journal of Molecular Biology · doi:10.1016/j.jmb.2025.169224 · Cited by 4 · see citing works
Self-citationJing, T., Shan, Z., Dinh, T., Biswas, A., Jang, S., Greenwood, J., Li, M., Zhang, Z., Gray, G., Shin, H. J., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.01.26.577436 · Cited by 4 · see citing works
Sayyed, S. K., Quraishi, M., Prabakaran, D. S., Chandrasekaran, B., Ramesh, T., Rajasekharan, S. K., Raorane, C. J., Sonawane, T., & Ravichandran, V. (2024) · Pharmaceuticals · doi:10.3390/ph18010030 · Cited by 3 · see citing works
Oligomerization of Retrovirus Integrases
Grandgenett, D. P., & Aihara, H. (2018) · Sub-cellular biochemistry/Subcellular biochemistry · doi:10.1007/978-981-10-8456-0_10 · Cited by 3 · see citing works
Ciubotaru, M., Musat, M. G., Surleac, M. D., Ionita, E., Petrescu, A., Abele, E., & Abele, R. (2019) · Current Medicinal Chemistry · doi:10.2174/0929867325666180406114405 · Cited by 3 · see citing works
Vulnerable targets in HIV-1 Pol for attenuation-based vaccine design
Ojwach, D. B. A., Madlala, P., Gordon, M. L., Ndung’u, T., & Mann, J. K. (2020) · Virology · doi:10.1016/j.virol.2020.12.003 · Cited by 3 · see citing works
Hao, M., Imamichi, T., & Chang, W. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25031809 · Cited by 1 · see citing works
Multimerization of HIV-1 integrase hinges on conserved SH3-docking platformsPreprint
Galilee, M., & Alian, A. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/301721
Carta, F., & Sechi, M. (2023) · Elsevier eBooks · doi:10.1016/b978-0-12-823974-2.00006-1
Retrointegration2023—Papers from the 7th International Conference on Retroviral Integration
Engelman, A., Grandgenett, D. P., Maertens, G. N., Yoder, K. E., & Kvaratskhelia, M. (2025) · Viruses · doi:10.3390/v17070879
HIV-1 Integrase During the Time: History of Drugs and Effort for the New Inhibitors’ Identification
Esposito, F., Saccoliti, F., Patacchini, E., & Santo, R. D. (2026) · Topics in medicinal chemistry · doi:10.1007/7355_2026_180
Protein‐Protein Interaction as an Efficient Target to Inhibit HIV‐1 Integrase
Zarghi, A., & Hajimahdi, Z. (2026) · Archiv der Pharmazie · doi:10.1002/ardp.70221
Mechanisms of HIV-1 assembly, release and maturation
Kleinpeter, A. B., & Freed, E. O. (2026) · Nature Reviews Microbiology · doi:10.1038/s41579-026-01327-6 · Cited by 1 · see citing works
Saccoliti, F., Patacchini, E., Cara, E., Zarbo, L., Messore, A., Albano, A., Ruggieri, G., Madia, V. N., Scipione, L., Costi, R., et al. (2026) · ChemMedChem · doi:10.1002/cmdc.70428
BindingDB (2020) · UC San Diego · doi:10.7270/q2pc352q
- Authors
- Gupta, K., Turkki, V., Sherrill-Mix, S., Hwang, Y., Eilers, G., Taylor, L., McDanal, C., Wang, P., Temelkoff, D., Nolte, R. T., Velthuisen, E., Jeffrey, J., Van Duyne, G. D., & Bushman, F. D.
- Affiliations
- University of Pennsylvania (US)
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Bushman, Frederic D.
- ORCID
- Venue
- PLOS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2016-12-09
- Volume
- 14
- Issue
- 12
- Pages
- e1002584
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- PMC
- PMC5147827
- OpenAlex
- W2559832357
- Cited by
- 68
- References
- 62
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 10 · 2023: 6 · 2022: 6 · 2021: 5 · 2020: 13 · 2019: 4 · 2018: 10 · 2017: 6
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- PLoS Biology (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institute of Allergy and Infectious Diseases (01 AI 052845, P30 AI045008)
- Instrumentarium Science Foundation
- Finnish Foundation for Cardiovascular Research
- Topics
- Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
- Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- HIV-1 integrase, integrase multimerization, protein aggregation, catalytic core domain, viral assembly, protein crystal structure
- MeSH terms
- Allosteric Regulation, Molecular Structure, HIV-1, HIV Integrase, HIV Integrase Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
