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

DOI: 10.1371/journal.ppat.1004459
PMID: 25356722

Authors: Amanda J. Price (Medical Research Council Laboratory of Molecular Biology) , David Jacques (MRC Laboratory of Molecular Biology) , William A. Mcewan (Medical Research Council Laboratory of Molecular Biology) , Adam J. Fletcher (Medical Research Council Laboratory of Molecular Biology) , Sebastian Essig (Medical Research Council Laboratory of Molecular Biology) , Jason W. Chin (Medical Research Council Laboratory of Molecular Biology) , Upul D. Halambage (Vanderbilt University School of Medicine) , Christopher Aiken (Vanderbilt University School of Medicine) , Leo C. James (Medical Research Council Laboratory of Molecular Biology)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Plos Pathogens , VOL 10 (10)

State: Published (Approved)
Published: October 2014
Diamond Proposal Number(s): 8547

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.

Journal Keywords: HIV-1; Viral packaging; Monomers; Drug interactions; Reverse transcription; Crystal structure; Hydrogen bonding; HeLa cells

Diamond Keywords: Human Immunodeficiency Virus (HIV); Viruses

Subject Areas: Biology and Bio-materials


Instruments: I04-1-Macromolecular Crystallography (fixed wavelength) , I24-Microfocus Macromolecular Crystallography

Added On: 20/03/2015 13:53

Discipline Tags:

Pathogens Infectious Diseases Health & Wellbeing Structural biology Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)