9d6d
Gag CA-SP1 immature lattice bound with Lenacapavir from enveloped virus like particles
Structural highlights
FunctionGAG_HV1N5 Matrix protein p17 targets Gag and Gag-Pol polyproteins to the plasma membrane via a multipartite membrane binding signal, that includes its myristoylated N-terminus. Also mediates nuclear localization of the preintegration complex. Implicated in the release from host cell mediated by Vpu. Capsid protein p24 forms the conical core of the virus that encapsulates the genomic RNA-nucleocapsid complex. Nucleocapsid protein p7 encapsulates and protects viral dimeric unspliced (genomic) RNA. Binds these RNAs through its zinc fingers. p6-gag plays a role in budding of the assembled particle by interacting with the host class E VPS proteins TSG101 and PDCD6IP/AIP1 (By similarity). Publication Abstract from PubMedHIV-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 in situ 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. Structural insights into inhibitor mechanisms on immature HIV-1 Gag lattice revealed by high-resolution in situ single-particle cryo-EM.,Wu C, Meuser ME, Rey JS, Meshkin H, Yang R, Devarkar SC, Freniere C, Shi J, Aiken C, Perilla JR, Xiong Y bioRxiv [Preprint]. 2024 Oct 9:2024.10.09.617473. doi: 10.1101/2024.10.09.617473. PMID:39416065[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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