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Nat Commun. 2016 Mar 4;7:10714. doi: 10.1038/ncomms10714.

Cyclophilin A stabilizes the HIV-1 capsid through a novel non-canonical binding site.

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Department of Structural Biology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
Pittsburgh Center for HIV Protein Interactions, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15260, USA.
Department of Physics and Beckman Institute, University of Illinois at Urbana-Champaign, Urbana, Illinois 61801, USA.
Department of Chemistry and Biochemistry, University of Delaware, Newark, Delaware 19716, USA.
Department of Physiology and Cell Biology, Ben-Gurion University of the Negev, Be'er-Sheva, 84105, Israel.
Department of Microbiology, University of Alabama at Birmingham, Birmingham Alabama 35294, USA.
Department of Pathology, Microbiology and Immunology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, USA.


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.

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