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 () and Tatyana Polenova ()
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Sucharita Sarkar: University of Delaware
Kaneil K. Zadrozny: University of Virginia School of Medicine
Roman Zadorozhnyi: University of Delaware
Ryan W. Russell: University of Delaware
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
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
Tatyana Polenova: University of Delaware

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-36569-y

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