Structural basis of HIV-1 maturation inhibitor binding and activity

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-Pornillos; Owen Pornillos; Angela M Gronenborn; Tatyana Polenova

doi:10.1038/s41467-023-36569-y

Structural basis of HIV-1 maturation inhibitor binding and activity

Nat Commun. 2023 Mar 4;14(1):1237. doi: 10.1038/s41467-023-36569-y.

Authors

Sucharita Sarkar^{1

2}, Kaneil K Zadrozny³, Roman Zadorozhnyi^{1

2}, Ryan W Russell^{1

2}, Caitlin M Quinn¹, Alex Kleinpeter⁴, Sherimay Ablan⁴, Hamed Meshkin¹, Juan R Perilla^{1

2}, Eric O Freed⁴, Barbie K Ganser-Pornillos⁵, Owen Pornillos⁶, Angela M Gronenborn^{7

8

9}, Tatyana Polenova^{10

11

12}

Affiliations

¹ Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA.
² Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA.
³ Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA.
⁴ HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, 21702-1201, USA.
⁵ Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA. bkg7q@virginia.edu.
⁶ Department of Molecular Physiology and Biological Physics, University of Virginia School of Medicine, Charlottesville, VA, 22908, USA. owp3a@virginia.edu.
⁷ Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA. amg100@pitt.edu.
⁸ Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. amg100@pitt.edu.
⁹ Department of Structural Biology, University of Pittsburgh School of Medicine, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. amg100@pitt.edu.
¹⁰ Department of Chemistry and Biochemistry, University of Delaware, Newark, DE, 19716, USA. tpolenov@udel.edu.
¹¹ Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, 1051 Biomedical Science Tower 3, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. tpolenov@udel.edu.
¹² Department of Structural Biology, University of Pittsburgh School of Medicine, 3501 Fifth Ave., Pittsburgh, PA, 15261, USA. tpolenov@udel.edu.

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 (CA_CTD), by binding to and stabilizing the CA_CTD-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 CA_CTD-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.

Publication types

Research Support, U.S. Gov't, Non-P.H.S.
Research Support, N.I.H., Extramural

MeSH terms

Capsid
Capsid Proteins
Catalysis
HIV-1*
Triterpenes*

Substances

bevirimat
Capsid Proteins
Triterpenes

Abstract

Publication types

MeSH terms

Substances

Grants and funding