4U0B

Hexamer HIV-1 CA in complex with CPSF6 peptide, P212121 crystal form

Summary for 4U0B

• Entry DOI: 10.2210/pdb4u0b/pdb
• Related: 4U0A
• Descriptor: Capsid protein p24, Cleavage and polyadenylation specificity factor subunit 6 (2 entities in total)
• Functional Keywords: capsid, complex, viral protein
• Biological source: Human immunodeficiency virus type 1 group M subtype B (HIV-1); More
• Cellular location: Matrix protein p17: Virion . Capsid protein p24: Virion . Nucleocapsid protein p7: Virion : P12493; Nucleus : Q16630
• Total number of polymer chains: 24
• Total formula weight: 324144.80

Authors

Price, A.J.,Jacques, D.A.,James, L.C. (deposition date: 2014-07-11, release date: 2014-11-12, Last modification date: 2024-10-23)

Primary citation

Price, A.J.,Jacques, D.A.,McEwan, W.A.,Fletcher, A.J.,Essig, S.,Chin, J.W.,Halambage, U.D.,Aiken, C.,James, L.C.
Host Cofactors and Pharmacologic Ligands Share an Essential Interface in HIV-1 Capsid That Is Lost upon Disassembly.
Plos Pathog., 10:e1004459-e1004459, 2014

PubMed 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.

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

Experimental method

X-RAY DIFFRACTION (2.8 Å)