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9D6C

Gag CA-SP1 immature lattice bound with Lenacapavir and Bevirimat from enveloped virus like particles

Summary for 9D6C
Entry DOI10.2210/pdb9d6c/pdb
EMDB information46593
DescriptorGag, N-[(1S)-1-(3-{4-chloro-3-[(methylsulfonyl)amino]-1-(2,2,2-trifluoroethyl)-1H-indazol-7-yl}-6-[3-methyl-3-(methylsulfonyl)but-1-yn-1-yl]pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl]-2-[(3bS,4aR)-5,5-difluoro-3-(trifluoromethyl)-3b,4,4a,5-tetrahydro-1H-cyclopropa[3,4]cyclopenta[1,2-c]pyrazol-1-yl]acetamide, 3alpha-[(3-carboxy-3-methylbutanoyl)oxy]-8alpha,9beta,10alpha,13alpha,17alpha,19beta-lup-20(29)-en-28-oic acid, ... (5 entities in total)
Functional Keywordshiv-1, gag, ca-sp1, inhibitor, virion assembly, virus like particle
Biological sourceHuman immunodeficiency virus type 1 group M subtype B (isolate HXB2)
Total number of polymer chains18
Total formula weight488751.65
Authors
Wu, C.,Meuser, M.E.,Xiong, Y. (deposition date: 2024-08-14, release date: 2024-10-30)
Primary citationWu, C.,Meuser, M.E.,Rey, J.S.,Meshkin, H.,Yang, R.,Devarkar, S.C.,Freniere, C.,Shi, J.,Aiken, C.,Perilla, J.R.,Xiong, Y.
Structural insights into inhibitor mechanisms on immature HIV-1 Gag lattice revealed by high-resolution in situ single-particle cryo-EM.
Biorxiv, 2024
Cited by
PubMed Abstract: HIV-1 inhibitors, such as Bevirimat (BVM) and Lenacapavir (LEN), block the production and maturation of infectious virions. However, their mechanisms remain unclear due to the absence of high-resolution structures for BVM complexes and LEN's structural data being limited to the mature capsid. Utilizing perforated virus-like particles (VLPs) produced from mammalian cells, we developed an approach to determine cryo-electron microscopy (cryo-EM) structures of HIV-1 with inhibitors. This allowed for the first structural determination of the native immature HIV-1 particle with BVM and LEN bound inside the VLPs at high resolutions. Our findings offer a more accurate model of BVM engaging the Gag lattice and, importantly, demonstrate that LEN not only binds the mature capsid but also targets the immature lattice in a distinct manner. The binding of LEN induces a conformational change in the capsid protein (CA) region and alters the architecture of the Gag lattice, which may affect the maturation process. These insights expand our understanding of the inhibitory mechanisms of BVM and LEN on HIV-1 and provide valuable clues for the design of future inhibitors.
PubMed: 39416065
DOI: 10.1101/2024.10.09.617473
PDB entries with the same primary citation
Experimental method
ELECTRON MICROSCOPY (2.1 Å)
Structure validation

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