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Molecular mechanism of HIV-1 gp120 mutations that reduce CD4 binding affinity.

Abstract
The interaction of the HIV-1 fusion protein gp120 with its cellular receptor CD4 represents a crucial step of the viral infection process, thus rendering gp120 a promising target for the intervention with anti-HIV drugs. Naturally occurring mutations of gp120, however, can decrease its affinity for anti-infective ligands like therapeutic antibodies or soluble CD4. To understand this phenomenon on a structural level, we performed molecular dynamics simulations of two gp120 variants (termed gp1203-2 and gp1202-1), which exhibit a significantly decreased binding of soluble CD4. In both variants, the exchange of a nonpolar residue by glutamate was identified as an important determinant for reduced binding. However, those glutamates are located at different sequence positions and affect different steps of the recognition process: E471 in gp1203-2 predominantly affects the CD4-bound conformation, whereas E372 in gp1202-1 mainly modulates the conformational sampling of free gp120. Despite these differences, there exists an interesting similarity between the two variants: both glutamates exert their function by modulating the conformation and interactions of glycine-rich motifs (G366-G367, G471-G473) resulting in an accumulation of binding incompetent gp120 conformations or a loss of intermolecular gp120-CD4 hydrogen bonds. Thus, the present data suggests that interference with the structure and dynamics of glycine-rich stretches might represent a more widespread mechanism, by which gp120 mutations reduce binding affinity. This knowledge should be helpful to predict the resistance of novel gp120 mutations or to design gp120-ligands with improved binding properties. An animated interactive 3D complement (I3DC) is available in Proteopedia at http://proteopedia.org/w/Journal:JBSD:41.
AuthorsKristin Kassler, Heinrich Sticht
JournalJournal of biomolecular structure & dynamics (J Biomol Struct Dyn) Vol. 32 Issue 1 Pg. 52-64 ( 2014) ISSN: 1538-0254 [Electronic] England
PMID23297802 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • CD4 Antigens
  • HIV Envelope Protein gp120
Topics
  • Binding Sites
  • CD4 Antigens (chemistry)
  • HIV Envelope Protein gp120 (chemistry, genetics)
  • HIV-1 (metabolism)
  • Humans
  • Molecular Dynamics Simulation
  • Mutation
  • Protein Conformation

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