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Structural basis of HIV-1 maturation inhibitor binding and activity

Author

Listed:
  • Sucharita Sarkar

    (University of Delaware
    University of Pittsburgh School of Medicine)

  • Kaneil K. Zadrozny

    (University of Virginia School of Medicine)

  • Roman Zadorozhnyi

    (University of Delaware
    University of Pittsburgh School of Medicine)

  • Ryan W. Russell

    (University of Delaware
    University of Pittsburgh School of Medicine)

  • Caitlin M. Quinn

    (University of Delaware)

  • Alex Kleinpeter

    (National Cancer Institute)

  • Sherimay Ablan

    (National Cancer Institute)

  • Hamed Meshkin

    (University of Delaware)

  • Juan R. Perilla

    (University of Delaware
    University of Pittsburgh School of Medicine)

  • Eric O. Freed

    (National Cancer Institute)

  • Barbie K. Ganser-Pornillos

    (University of Virginia School of Medicine)

  • Owen Pornillos

    (University of Virginia School of Medicine)

  • Angela M. Gronenborn

    (University of Delaware
    University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

  • Tatyana Polenova

    (University of Delaware
    University of Pittsburgh School of Medicine
    University of Pittsburgh School of Medicine)

Abstract

HIV-1 maturation inhibitors (MIs), Bevirimat (BVM) and its analogs interfere with the catalytic cleavage of spacer peptide 1 (SP1) from the capsid protein C-terminal domain (CACTD), by binding to and stabilizing the CACTD-SP1 region. MIs are under development as alternative drugs to augment current antiretroviral therapies. Although promising, their mechanism of action and associated virus resistance pathways remain poorly understood at the molecular, biochemical, and structural levels. We report atomic-resolution magic-angle-spinning NMR structures of microcrystalline assemblies of CACTD-SP1 complexed with BVM and/or the assembly cofactor inositol hexakisphosphate (IP6). Our results reveal a mechanism by which BVM disrupts maturation, tightening the 6-helix bundle pore and quenching the motions of SP1 and the simultaneously bound IP6. In addition, BVM-resistant SP1-A1V and SP1-V7A variants exhibit distinct conformational and binding characteristics. Taken together, our study provides a structural explanation for BVM resistance as well as guidance for the design of new MIs.

Suggested Citation

  • Sucharita Sarkar & Kaneil K. Zadrozny & Roman Zadorozhnyi & Ryan W. Russell & Caitlin M. Quinn & Alex Kleinpeter & Sherimay Ablan & Hamed Meshkin & Juan R. Perilla & Eric O. Freed & Barbie K. Ganser-P, 2023. "Structural basis of HIV-1 maturation inhibitor binding and activity," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-36569-y
    DOI: 10.1038/s41467-023-36569-y
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    References listed on IDEAS

    as
    1. Mingzhang Wang & Caitlin M. Quinn & Juan R. Perilla & Huilan Zhang & Randall Shirra Jr. & Guangjin Hou & In-Ja Byeon & Christopher L. Suiter & Sherimay Ablan & Emiko Urano & Theodore J. Nitz & Christo, 2017. "Quenching protein dynamics interferes with HIV capsid maturation," Nature Communications, Nature, vol. 8(1), pages 1-12, December.
    2. Robert A. Dick & Kaneil K. Zadrozny & Chaoyi Xu & Florian K. M. Schur & Terri D. Lyddon & Clifton L. Ricana & Jonathan M. Wagner & Juan R. Perilla & Barbie K. Ganser-Pornillos & Marc C. Johnson & Owen, 2018. "Inositol phosphates are assembly co-factors for HIV-1," Nature, Nature, vol. 560(7719), pages 509-512, August.
    3. Robert A. Dick & Kaneil K. Zadrozny & Chaoyi Xu & Florian K. M. Schur & Terri D. Lyddon & Clifton L. Ricana & Jonathan M. Wagner & Juan R. Perilla & Barbie K. Ganser-Pornillos & Marc C. Johnson & Owen, 2018. "Author Correction: Inositol phosphates are assembly co-factors for HIV-1," Nature, Nature, vol. 563(7731), pages 22-22, November.
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