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：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2022 · DOI：10.1101/2022.08.25.505312 · 被引用次数：26 · 研究领域：HIV Research and Treatment、RNA and protein synthesis mechanisms、HIV/AIDS drug development and treatment

Abstract Upon entry into a new host cell, the HIV-1 capsid performs multiple essential functions, which include shielding the genome from innate immune sensors 1 , promoting reverse transcription 2 and transporting the core from the entry site at the plasma membrane to the integration site inside the nucleus 3,4 . The HIV-1 capsid is a fullerene cone made of hexamers and pentamers of the viral CA protein 5,6 . The two types of capsomers are quasi-equivalent, with the same structural elements mediating distinct inter-subunit contacts. In other studied quasi-equivalent viruses, the capacity of genetically identical subunits to form hexamers and pentamers is conferred by molecular switches. Such a switch has not been previously found in retroviral CA proteins. Here, we report cryoEM structures of the HIV-1 CA pentamer within assembled in vitro capsids at nominal resolutions of 2.4-3.4 Å. Comparison with the hexamer identified an internal loop that adopts distinct conformations, 3 10 helix in the pentamer and random coil in the hexamer. Designed manipulations of the coil/helix configuration allowed us to control pentamer and hexamer formation in a predictable manner, thus proving its function as a molecular switch. Importantly, the switch controls not only fullerene cone assembly, but also the capsid’s capacity to bind post-entry host factors that are critical for viral replication. Furthermore, the switch forms part of the binding site of the new ultra-potent HIV-1 inhibitor, le...