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The host cell factor cyclophilin A (CypA) interacts directly with the HIV-1 capsid and regulates viral infectivity. Although the crystal structure of CypA in complex with the N-terminal domain of the HIV-1 capsid protein (CA) has been known for nearly two decades, how CypA interacts with the viral capsid and modulates HIV-1 infectivity remains unclear. We determined the cryoEM structure of CypA in complex with the assembled HIV-1 capsid at 8-Å resolution. The structure exhibits a distinct CypA-binding pattern in which CypA selectively bridges the two CA hexamers along the direction of highest curvature. EM-guided all-atom molecular dynamics simulations and solid-state NMR further reveal that the CypA-binding pattern is achieved by single-CypA molecules simultaneously interacting with two CA subunits, in different hexamers, through a previously uncharacterized non-canonical interface. These results provide new insights into how CypA stabilizes the HIV-1 capsid and is recruited to facilitate HIV-1 infection.

Original publication

DOI

10.1038/ncomms10714

Type

Journal article

Journal

Nat Commun

Publication Date

04/03/2016

Volume

7

Keywords

Capsid Proteins, Catalytic Domain, Computer Simulation, Cyclophilin A, Escherichia coli, Gene Expression Regulation, Viral, HIV-1, Magnetic Resonance Spectroscopy, Models, Molecular, Protein Binding, Protein Conformation, Virus Assembly