7R7P

Immature HIV-1 CACTD-SP1 lattice with Bevirimat (BVM) and Inositol hexakisphosphate (IP6)

Summary for 7R7P

• Entry DOI: 10.2210/pdb7r7p/pdb
• NMR Information: BMRB: 30929
• Descriptor: Gag polyprotein, INOSITOL HEXAKISPHOSPHATE, 3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13alpha,17alpha,19beta-lup-20(29)-en-28-oic acid (3 entities in total)
• Functional Keywords: hiv-1 capsid, maturation inhibitors, hiv-aids, protein binding
• Biological source: Human immunodeficiency virus 1
• Total number of polymer chains: 6
• Total formula weight: 67812.89

Authors

Sarkar, S.,Zadrozny, K.K.,Zadorozhnyi, R.,Russell, R.W.,Quinn, C.M.,Kleinpeter, A.,Ablan, S.,Meshkin, H.,Perilla, J.R.,Ganser-Pornillos, B.K.,Pornillos, O.,Freed, E.O.,Gronenborn, A.M.,Polenova, T. (deposition date: 2021-06-25, release date: 2023-02-15, Last modification date: 2024-05-15)

Primary citation

Sarkar, S.,Zadrozny, K.K.,Zadorozhnyi, R.,Russell, R.W.,Quinn, C.M.,Kleinpeter, A.,Ablan, S.,Meshkin, H.,Perilla, J.R.,Freed, E.O.,Ganser-Pornillos, B.K.,Pornillos, O.,Gronenborn, A.M.,Polenova, T.
Structural basis of HIV-1 maturation inhibitor binding and activity.
Nat Commun, 14:1237-1237, 2023

PubMed 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.

PubMed: 36871077
DOI: 10.1038/s41467-023-36569-y

Experimental method

SOLID-STATE NMR