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Structural basis for strand-transfer inhibitor binding to HIV intasomes.

Passos DO, Li M, Jóźwik IK, Zhao XZ, Santos-Martins D, Yang R, Smith SJ, Jeon Y, Forli S, Hughes SH, Burke TR, Craigie R, Lyumkis D
Science 367 810-814 (2020)
Related entries: 6puw, 6puy, 6puz, 6v3k

Cited: 40 times
EuropePMC logo PMID: 32001521

Abstract

The HIV intasome is a large nucleoprotein assembly that mediates the integration of a DNA copy of the viral genome into host chromatin. Intasomes are targeted by the latest generation of antiretroviral drugs, integrase strand-transfer inhibitors (INSTIs). Challenges associated with lentiviral intasome biochemistry have hindered high-resolution structural studies of how INSTIs bind to their native drug target. Here, we present high-resolution cryo-electron microscopy structures of HIV intasomes bound to the latest generation of INSTIs. These structures highlight how small changes in the integrase active site can have notable implications for drug binding and design and provide mechanistic insights into why a leading INSTI retains efficacy against a broad spectrum of drug-resistant variants. The data have implications for expanding effective treatments available for HIV-infected individuals.

Reviews - 6put mentioned but not cited (4)

  1. Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs. Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR, Hughes SH. Viruses 13 205 (2021)
  2. Multimodal Functionalities of HIV-1 Integrase. Engelman AN, Kvaratskhelia M. Viruses 14 926 (2022)
  3. Close-up: HIV/SIV intasome structures shed new light on integrase inhibitor binding and viral escape mechanisms. Engelman AN, Cherepanov P. FEBS J 288 427-433 (2021)
  4. The C-Terminal Domain of HIV-1 Integrase: A Swiss Army Knife for the Virus? Rocchi C, Gouet P, Parissi V, Fiorini F. Viruses 14 1397 (2022)

Articles - 6put mentioned but not cited (6)

  1. Structural basis for strand-transfer inhibitor binding to HIV intasomes. Passos DO, Li M, Jóźwik IK, Zhao XZ, Santos-Martins D, Yang R, Smith SJ, Jeon Y, Forli S, Hughes SH, Burke TR, Craigie R, Lyumkis D. Science 367 810-814 (2020)
  2. HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants. Smith SJ, Zhao XZ, Passos DO, Pye VE, Cherepanov P, Lyumkis D, Burke TR, Hughes SH. ACS Infect Dis 7 1469-1482 (2021)
  3. Influence of the amino-terminal sequence on the structure and function of HIV integrase. Eilers G, Gupta K, Allen A, Zhou J, Hwang Y, Cory MB, Bushman FD, Van Duyne G. Retrovirology 17 28 (2020)
  4. Retroviral integrase: Structure, mechanism, and inhibition. Passos DO, Li M, Craigie R, Lyumkis D. Enzymes 50 249-300 (2021)
  5. A snapshot on HIV-1 evolution through the identification of phylogenetic-specific properties of HIV-1 integrases M/O. Toccafondi E, Kanja M, Winter F, Lener D, Negroni M. PLoS Pathog 19 e1011207 (2023)
  6. research-article Oligomeric HIV-1 Integrase Structures Reveal Functional Plasticity for Intasome Assembly and RNA Binding. Jing T, Shan Z, Dinh T, Biswas A, Jang S, Greenwood J, Li M, Zhang Z, Gray G, Shin HJ, Zhou B, Passos D, Aiyer S, Li Z, Craigie R, Engelman AN, Kvaratskhelia M, Lyumkis D. bioRxiv 2024.01.26.577436 (2024)


Reviews citing this publication (8)

  1. Drug Design Strategies to Avoid Resistance in Direct-Acting Antivirals and Beyond. Matthew AN, Leidner F, Lockbaum GJ, Henes M, Zephyr J, Hou S, Rao DN, Timm J, Rusere LN, Ragland DA, Paulsen JL, Prachanronarong K, Soumana DI, Nalivaika EA, Kurt Yilmaz N, Ali A, Schiffer CA. Chem Rev 121 3238-3270 (2021)
  2. Structure and function of retroviral integrase. Maertens GN, Engelman AN, Cherepanov P. Nat Rev Microbiol 20 20-34 (2022)
  3. Cryo-EM as a powerful tool for drug discovery. Van Drie JH, Tong L. Bioorg Med Chem Lett 30 127524 (2020)
  4. Avoiding Drug Resistance in HIV Reverse Transcriptase. Cilento ME, Kirby KA, Sarafianos SG. Chem Rev 121 3271-3296 (2021)
  5. Structural Biology of HIV Integrase Strand Transfer Inhibitors. Jóźwik IK, Passos DO, Lyumkis D. Trends Pharmacol Sci 41 611-626 (2020)
  6. A clinical review of HIV integrase strand transfer inhibitors (INSTIs) for the prevention and treatment of HIV-1 infection. Zhao AV, Crutchley RD, Guduru RC, Ton K, Lam T, Min AC. Retrovirology 19 22 (2022)
  7. Long-Acting Cabotegravir for HIV/AIDS Prophylaxis. Engelman KD, Engelman AN. Biochemistry 60 1731-1740 (2021)
  8. Tools for visualizing and analyzing Fourier space sampling in Cryo-EM. Baldwin PR, Lyumkis D. Prog Biophys Mol Biol 160 53-65 (2021)

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  1. Defining the substrate envelope of SARS-CoV-2 main protease to predict and avoid drug resistance. Shaqra AM, Zvornicanin SN, Huang QYJ, Lockbaum GJ, Knapp M, Tandeske L, Bakan DT, Flynn J, Bolon DNA, Moquin S, Dovala D, Kurt Yilmaz N, Schiffer CA. Nat Commun 13 3556 (2022)
  2. Cryo-EM structure of the deltaretroviral intasome in complex with the PP2A regulatory subunit B56γ. Barski MS, Minnell JJ, Hodakova Z, Pye VE, Nans A, Cherepanov P, Maertens GN. Nat Commun 11 5043 (2020)
  3. HIV-1 Integrase Inhibitors That Are Active against Drug-Resistant Integrase Mutants. Smith SJ, Zhao XZ, Passos DO, Lyumkis D, Burke TR, Hughes SH. Antimicrob Agents Chemother 64 e00611-20 (2020)
  4. Long Dissociation of Bictegravir from HIV-1 Integrase-DNA Complexes. White KL, Osman N, Cuadra-Foy E, Brenner BG, Shivakumar D, Campigotto F, Tsiang M, Morganelli PA, Novikov N, Lazerwith SE, Jin H, Niedziela-Majka A. Antimicrob Agents Chemother 65 AAC.02406-20 (2023)
  5. Cryo-EM structure of the Rous sarcoma virus octameric cleaved synaptic complex intasome. Pandey KK, Bera S, Shi K, Rau MJ, Oleru AV, Fitzpatrick JAJ, Engelman AN, Aihara H, Grandgenett DP. Commun Biol 4 330 (2021)
  6. HIV-induced membraneless organelles orchestrate post-nuclear entry steps. Scoca V, Morin R, Collard M, Tinevez JY, Di Nunzio F. J Mol Cell Biol 14 mjac060 (2023)
  7. A large expert-curated cryo-EM image dataset for machine learning protein particle picking. Dhakal A, Gyawali R, Wang L, Cheng J. Sci Data 10 392 (2023)
  8. Complex of HIV-1 Integrase with Cellular Ku Protein: Interaction Interface and Search for Inhibitors. Ilgova E, Galkin S, Khrenova M, Serebryakova M, Gottikh M, Anisenko A. Int J Mol Sci 23 2908 (2022)
  9. The G118R plus R263K Combination of Integrase Mutations Associated with Dolutegravir-Based Treatment Failure Reduces HIV-1 Replicative Capacity and Integration. Xiao MA, Cleyle J, Yoo S, Forrest M, Krullaars Z, Pham HT, Mesplède T. Antimicrob Agents Chemother 67 e0138622 (2023)
  10. Allosteric Integrase Inhibitor Influences on HIV-1 Integration and Roles of LEDGF/p75 and HDGFL2 Host Factors. Singh PK, Li W, Bedwell GJ, Fadel HJ, Poeschla EM, Engelman AN. Viruses 14 1883 (2022)
  11. B-to-A transition in target DNA during retroviral integration. Jóźwik IK, Li W, Zhang DW, Wong D, Grawenhoff J, Ballandras-Colas A, Aiyer S, Cherepanov P, Engelman AN, Lyumkis D. Nucleic Acids Res 50 8898-8918 (2022)
  12. Human Three Prime Repair Exonuclease 1 Promotes HIV-1 Integration by Preferentially Degrading Unprocessed Viral DNA. Davids BO, Balasubramaniam M, Sapp N, Prakash P, Ingram S, Li M, Craigie R, Hollis T, Pandhare J, Dash C. J Virol 95 e0055521 (2021)
  13. Localization and functions of native and eGFP-tagged capsid proteins in HIV-1 particles. Francis AC, Cereseto A, Singh PK, Shi J, Poeschla E, Engelman AN, Aiken C, Melikyan GB. PLoS Pathog 18 e1010754 (2022)
  14. Structural basis for the inhibition of HTLV-1 integration inferred from cryo-EM deltaretroviral intasome structures. Barski MS, Vanzo T, Zhao XZ, Smith SJ, Ballandras-Colas A, Cronin NB, Pye VE, Hughes SH, Burke TR, Cherepanov P, Maertens GN. Nat Commun 12 4996 (2021)
  15. A Practical Approach to Bicyclic Carbamoyl Pyridones with Application to the Synthesis of HIV-1 Integrase Strand Transfer Inhibitors. Mahajan PS, Smith SJ, Hughes SH, Zhao X, Burke TR. Molecules 28 1428 (2023)
  16. The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function. Singer MR, Dinh T, Levintov L, Annamalai AS, Rey JS, Briganti L, Cook NJ, Pye VE, Taylor IA, Kim K, Engelman AN, Kim B, Perilla JR, Kvaratskhelia M, Cherepanov P. mBio 14 e0356022 (2023)
  17. DNA strand breaks and gaps target retroviral intasome binding and integration. Senavirathne G, London J, Gardner A, Fishel R, Yoder KE. Nat Commun 14 7072 (2023)
  18. Evidence for Disruption of Mg2+ Pair as a Resistance Mechanism Against HIV-1 Integrase Strand Transfer Inhibitors. Machado LA, Guimarães ACR. Front Mol Biosci 7 170 (2020)
  19. Liquid-assisted mechanochemical synthesis, crystallographic, theoretical and molecular docking study on HIV instasome of novel copper complexes: (µ-acetato)-bis(2,2'-bipyridine)-copper and bromidotetrakis(2-methyl-1H-imidazole)-copper bromide. Jaryal R, Khan SA. Biometals 36 975-996 (2023)
  20. Modulation of the functional interfaces between retroviral intasomes and the human nucleosome. Mauro E, Lapaillerie D, Tumiotto C, Charlier C, Martins F, Sousa SF, Métifiot M, Weigel P, Yamatsugu K, Kanai M, Munier-Lehmann H, Richetta C, Maisch M, Dutrieux J, Batisse J, Ruff M, Delelis O, Lesbats P, Parissi V. mBio 14 e0108323 (2023)
  21. Molecular determinants for Rous sarcoma virus intasome assemblies involved in retroviral integration. Bera S, Shi K, Aihara H, Grandgenett DP, Pandey KK. J Biol Chem 299 104730 (2023)
  22. The Discovery of Indole-2-carboxylic Acid Derivatives as Novel HIV-1 Integrase Strand Transfer Inhibitors. Wang YC, Zhang WL, Zhang RH, Liu CH, Zhao YL, Yan GY, Liao SG, Li YJ, Zhou M. Molecules 28 8020 (2023)


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