A molecular switch modulates assembly and host factor binding of the HIV-1 capsid

作者：Randall T. Schirra, Nayara F. B. dos Santos, Kaneil K. Zadrozny, Iga Kucharska, Barbie K. Ganser‐Pornillos, Owen Pornillos · 发表于：Nature Structural & Molecular Biology · 年份：2023 · DOI：10.1038/s41594-022-00913-5 · 被引用次数：47 · 研究领域：HIV Research and Treatment、Protein Structure and Dynamics、HIV/AIDS drug development and treatment

Abstract The HIV-1 capsid is a fullerene cone made of quasi-equivalent hexamers and pentamers of the viral CA protein. Typically, quasi-equivalent assembly of viral capsid subunits is controlled by a molecular switch. Here, we identify a Thr-Val-Gly-Gly motif that modulates CA hexamer/pentamer switching by folding into a 3 10 helix in the pentamer and random coil in the hexamer. Manipulating the coil/helix configuration of the motif allowed us to control pentamer and hexamer formation in a predictable manner, thus proving its function as a molecular switch. Importantly, the switch also remodels the common binding site for host factors that are critical for viral replication and the new ultra-potent HIV-1 inhibitor lenacapavir. This study reveals that a critical assembly element also modulates the post-assembly and viral replication functions of the HIV-1 capsid and provides new insights on capsid function and inhibition.