| Molecular mechanism of HIV-1 gp120 mutations that reduce CD4 binding affinity. | |
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MedLine Citation:
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PMID: 23297802 Owner: NLM Status: Publisher |
Abstract/OtherAbstract:
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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 gp120(3-2) and gp120(2-1)), which exhibit a significantly decreased binding of soluble CD4. In both variants, the exchange of a nonpolar residue byglutamate 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 gp120(3-2) predominantly affects the CD4-bound conformation, whereas E372 in gp120(2-1) 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. |
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Authors:
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Kristin Kassler; Heinrich Sticht |
Publication Detail:
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Type: JOURNAL ARTICLE Date: 2013-1-9 |
Journal Detail:
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Title: Journal of biomolecular structure & dynamics Volume: - ISSN: 1538-0254 ISO Abbreviation: J. Biomol. Struct. Dyn. Publication Date: 2013 Jan |
Date Detail:
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Created Date: 2013-1-10 Completed Date: - Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 8404176 Medline TA: J Biomol Struct Dyn Country: - |
Other Details:
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Languages: ENG Pagination: - Citation Subset: - |
Affiliation:
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a Bioinformatics , Institute for Biochemistry, Friedrich-Alexander-Universität Erlangen-Nürnberg , Fahrstrasse 17 , Erlangen , 91054 , Germany. |
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From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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