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

Back

Structural basis of HIV-1 maturation inhibitor binding and activity

Journal article

Open access

Peer reviewed

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, …

Nature communications, Vol.14(1), pp.1237-1237

03/04/2023

DOI: 10.1038/s41467-023-36569-y

PMCID: PMC9985623

PMID: 36871077

Files and links (1)

url

https://doi.org/10.1038/s41467-023-36569-yView

Published (Version of record) Open Access

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 ), by binding to and stabilizing the CA -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 -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.

Capsid

Capsid Proteins

Catalysis

HIV-1

Triterpenes

Details

Title: Subtitle: Structural basis of HIV-1 maturation inhibitor binding and activity
Creators: Sucharita Sarkar - University of Delaware
Kaneil K Zadrozny - University of Virginia
Roman Zadorozhnyi - University of Delaware
Ryan W Russell - University of Delaware
Caitlin M Quinn - University of Delaware
Alex Kleinpeter - Center for Cancer Research
Sherimay Ablan - Center for Cancer Research
Hamed Meshkin - University of Delaware
Juan R Perilla - University of Delaware
Eric O Freed - Center for Cancer Research
Barbie K Ganser-Pornillos - University of Virginia
Owen Pornillos - University of Virginia
Angela M Gronenborn - University of Pittsburgh
Tatyana Polenova - University of Pittsburgh
Resource Type: Journal article
Publication Details: Nature communications, Vol.14(1), pp.1237-1237
DOI: 10.1038/s41467-023-36569-y
PMID: 36871077
PMCID: PMC9985623
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Grant note: R01 AI129678 / NIAID NIH HHS R01 AI157843 / NIAID NIH HHS
Language: English
Date published: 03/04/2023
Academic Unit: Microbiology and Immunology
Record Identifier: 9984827337502771

Metrics

2 Record Views

18 Times Cited - Web of Science

See more details