Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly
- Publication Type:
- Journal Article
- Citation:
- PLoS Pathogens, 2014, 10 (10)
- Issue Date:
- 2014-01-01
Open Access
Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Price, AJ | en_US |
dc.contributor.author |
Jacques, DA |
en_US |
dc.contributor.author | McEwan, WA | en_US |
dc.contributor.author | Fletcher, AJ | en_US |
dc.contributor.author | Essig, S | en_US |
dc.contributor.author | Chin, JW | en_US |
dc.contributor.author | Halambage, UD | en_US |
dc.contributor.author | Aiken, C | en_US |
dc.contributor.author | James, LC | en_US |
dc.date.available | 2014-09-10 | en_US |
dc.date.issued | 2014-01-01 | en_US |
dc.identifier.citation | PLoS Pathogens, 2014, 10 (10) | en_US |
dc.identifier.issn | 1553-7366 | en_US |
dc.description.abstract | © 2014 Price et al. 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. | en_US |
dc.relation | http://purl.org/au-research/grants/nhmrc/APP1036521 | |
dc.relation.ispartof | PLoS Pathogens | en_US |
dc.relation.isbasedon | 10.1371/journal.ppat.1004459 | en_US |
dc.subject.classification | Virology | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | HIV-1 | en_US |
dc.subject.mesh | Virion | en_US |
dc.subject.mesh | Capsid | en_US |
dc.subject.mesh | HIV Infections | en_US |
dc.subject.mesh | Indoles | en_US |
dc.subject.mesh | Polycyclic Compounds | en_US |
dc.subject.mesh | Phenylalanine | en_US |
dc.subject.mesh | Nuclear Pore Complex Proteins | en_US |
dc.subject.mesh | mRNA Cleavage and Polyadenylation Factors | en_US |
dc.subject.mesh | Capsid Proteins | en_US |
dc.subject.mesh | Anti-HIV Agents | en_US |
dc.subject.mesh | Ligands | en_US |
dc.subject.mesh | Reverse Transcription | en_US |
dc.subject.mesh | Binding Sites | en_US |
dc.subject.mesh | Protein Structure, Tertiary | en_US |
dc.subject.mesh | Protein Binding | en_US |
dc.subject.mesh | Mutation | en_US |
dc.subject.mesh | Models, Molecular | en_US |
dc.subject.mesh | Models, Structural | en_US |
dc.subject.mesh | Polymerization | en_US |
dc.subject.mesh | Anti-HIV Agents | en_US |
dc.subject.mesh | Binding Sites | en_US |
dc.subject.mesh | Capsid | en_US |
dc.subject.mesh | Capsid Proteins | en_US |
dc.subject.mesh | HIV Infections | en_US |
dc.subject.mesh | HIV-1 | en_US |
dc.subject.mesh | Humans | en_US |
dc.subject.mesh | Indoles | en_US |
dc.subject.mesh | Ligands | en_US |
dc.subject.mesh | Models, Molecular | en_US |
dc.subject.mesh | Models, Structural | en_US |
dc.subject.mesh | Mutation | en_US |
dc.subject.mesh | Nuclear Pore Complex Proteins | en_US |
dc.subject.mesh | Phenylalanine | en_US |
dc.subject.mesh | Polycyclic Compounds | en_US |
dc.subject.mesh | Polymerization | en_US |
dc.subject.mesh | Protein Binding | en_US |
dc.subject.mesh | Protein Structure, Tertiary | en_US |
dc.subject.mesh | Reverse Transcription | en_US |
dc.subject.mesh | Virion | en_US |
dc.subject.mesh | mRNA Cleavage and Polyadenylation Factors | en_US |
dc.title | Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly | en_US |
dc.type | Journal Article | |
utslib.description.version | Published | en_US |
utslib.citation.volume | 10 | en_US |
utslib.citation.volume | 10 | en_US |
utslib.for | 0605 Microbiology | en_US |
utslib.for | 1115 Pharmacology and Pharmaceutical Sciences | en_US |
utslib.for | 0605 Microbiology | en_US |
utslib.for | 1107 Immunology | en_US |
utslib.for | 1108 Medical Microbiology | en_US |
pubs.embargo.period | Not known | en_US |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
utslib.copyright.status | open_access | |
pubs.issue | 10 | en_US |
pubs.publication-status | Published | en_US |
pubs.volume | 10 | en_US |
Files in This Item:
Filename | Description | Size | |||
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ContentServer (51).pdf | Published Version | 5.06 MB | Adobe PDF |
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Abstract:
© 2014 Price et al. 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.
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