Residues in the HIV-1 capsid assembly inhibitor binding site are essential for maintaining the assembly-competent quaternary structure of the capsid protein

J Biol Chem. 2008 Nov 14;283(46):32024-33. doi: 10.1074/jbc.M804230200. Epub 2008 Sep 4.


Morphogenesis of infectious HIV-1 involves budding of immature virions followed by proteolytic disassembly of the Gag protein shell and subsequent assembly of processed capsid proteins (CA) into the mature HIV-1 core. The dimeric interface between C-terminal domains of CA (C-CA) has been shown to be important for both immature and mature assemblies. We previously reported a CA-binding peptide (CAI) that blocks both assembly steps in vitro. The three-dimensional structure of the C-CA/CAI complex revealed an allosteric effect of CAI that alters the C-CA dimer interface. Based on this structure, we now investigated the phenotypes of mutations in the binding pocket. CA variants carrying mutations Y169A, L211A, or L211S had a reduced affinity for CAI and were unable to form mature-like particles in vitro. These mutations also blocked morphological conversion to mature virions in tissue culture and abolished infectivity. X-ray crystallographic analyses of the variant C-CA domains revealed that these alterations induced the same allosteric change at the dimer interface observed in the C-CA/CAI complex. These results point to a role of key interactions between conserved amino acids in the CAI binding pocket of C-CA in maintaining the correct conformation necessary for mature core assembly.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Binding Sites
  • Capsid / drug effects*
  • Capsid / metabolism*
  • Capsid Proteins / chemistry*
  • Capsid Proteins / genetics
  • Capsid Proteins / metabolism*
  • Capsid Proteins / ultrastructure
  • Cell Line
  • Conserved Sequence
  • Crystallography, X-Ray
  • HIV-1 / chemistry*
  • HIV-1 / drug effects
  • HIV-1 / metabolism*
  • HIV-1 / ultrastructure
  • Humans
  • Microscopy, Electron
  • Models, Molecular
  • Molecular Sequence Data
  • Mutation / genetics
  • Peptides / pharmacology
  • Protein Structure, Quaternary
  • Sequence Alignment
  • Virus Assembly / drug effects*


  • Capsid Proteins
  • Peptides

Associated data

  • PDB/3DPH
  • PDB/3DS0
  • PDB/3DS1
  • PDB/3DS2
  • PDB/3DS3
  • PDB/3DS4
  • PDB/3DS5
  • PDB/3DTJ