Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly

Cullen, B. R., Price, A. J., Jacques, D. A., McEwan, W. A., Fletcher, A. J., Essig, S., Chin, J. W., Halambage, U. D., Aiken, C. and James, L. C. (2014) Host cofactors and pharmacologic ligands share an essential interface in HIV-1 capsid that is lost upon disassembly. PLoS Pathogens, 10(10), e1004459. (doi: 10.1371/journal.ppat.1004459) (PMID:25356722) (PMCID:PMC4214760)

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Abstract

The HIV-1 capsid is involved in all infectious steps from reverse transcription to integration site selection, and is the target of multiple host cell and pharmacologic ligands. However, structural studies have been limited to capsid monomers (CA), and the mechanistic basis for how these ligands influence infection is not well understood. Here we show that a multi-subunit interface formed exclusively within CA hexamers mediates binding to linear epitopes within cellular cofactors NUP153 and CPSF6, and is competed for by the antiretroviral compounds PF74 and BI-2. Each ligand is anchored via a shared phenylalanine-glycine (FG) motif to a pocket within the N-terminal domain of one monomer, and all but BI-2 also make essential interactions across the N-terminal domain: C-terminal domain (NTD:CTD) interface to a second monomer. Dissociation of hexamer into CA monomers prevents high affinity interaction with CPSF6 and PF74, and abolishes binding to NUP153. The second interface is conformationally dynamic, but binding of NUP153 or CPSF6 peptides is accommodated by only one conformation. NUP153 and CPSF6 have overlapping binding sites, but each makes unique CA interactions that, when mutated selectively, perturb cofactor dependency. These results reveal that multiple ligands share an overlapping interface in HIV-1 capsid that is lost upon viral disassembly

Item Type:Articles
Additional Information:Funding: This work was funded by the Medical Research Council (UK; U105181010), the European Research Council (281627 ­IAI), and the National Institutes of Health (USA; R01 AI089401). DAJ was supported by an NHMRC Early Career Fellowship (GNT1036521) and AJP by a Research Fellowship from Emmanuel College, Cambridge.
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Fletcher, Dr Adam
Authors: Cullen, B. R., Price, A. J., Jacques, D. A., McEwan, W. A., Fletcher, A. J., Essig, S., Chin, J. W., Halambage, U. D., Aiken, C., and James, L. C.
College/School:College of Medical Veterinary and Life Sciences > Institute of Infection Immunity and Inflammation
Journal Name:PLoS Pathogens
Publisher:Public Library of Science
ISSN:1553-7366
ISSN (Online):1553-7374
Copyright Holders:Copyright: © 2014 Price et al.
First Published:First published in PLoS Pathogens 10:e1004459
Publisher Policy:Reproduced under a Creative Commons licence

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