Kaßler K, Sticht H (2014)
Publication Type: Journal article
Publication year: 2014
Publisher: Taylor & Francis
Book Volume: 32
Pages Range: 52-64
Journal Issue: 1
DOI: 10.1080/07391102.2012.746946
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.
APA:
Kaßler, K., & Sticht, H. (2014). Molecular mechanism of HIV-1 gp120 mutations that reduce CD4 binding affinity. Journal of Biomolecular Structure & Dynamics, 32(1), 52-64. https://dx.doi.org/10.1080/07391102.2012.746946
MLA:
Kaßler, Kristin, and Heinrich Sticht. "Molecular mechanism of HIV-1 gp120 mutations that reduce CD4 binding affinity." Journal of Biomolecular Structure & Dynamics 32.1 (2014): 52-64.
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