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Putative cholesterol‐binding sites in human immunodeficiency virus (HIV) coreceptors CXCR4 and CCR5
Author(s) -
Zhukovsky Mikhail A.,
Lee PoHsien,
Ott Albrecht,
Helms Volkhard
Publication year - 2013
Publication title -
proteins: structure, function, and bioinformatics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.699
H-Index - 191
eISSN - 1097-0134
pISSN - 0887-3585
DOI - 10.1002/prot.24211
Subject(s) - cholesterol , biology , biochemistry , lipid raft , docking (animal) , binding site , receptor , tyrosine , cell membrane , cell , medicine , nursing
Abstract Using molecular docking, we identified a cholesterol‐binding site in the groove between transmembrane helices 1 and 7 near the inner membrane‐water interface of the G protein‐coupled receptor CXCR4, a coreceptor for HIV entry into cells. In this docking pose, the amino group of lysine K67 establishes a hydrogen bond with the hydroxyl group of cholesterol, whereas tyrosine Y302 stacks with cholesterol by its aromatic side chain, and a number of residues form hydrophobic contacts with cholesterol. Sequence alignment showed that a similar putative cholesterol‐binding site is also present in CCR5, another HIV coreceptor. We suggest that the interaction of cholesterol with these putative cholesterol‐binding sites in CXCR4 and CCR5 is responsible for the presence of these receptors in lipid rafts, for the effect of cholesterol on their conformational stability and function, and for the role that cell cholesterol plays in the cell entry of HIV strains that use these membrane proteins as coreceptors. We propose that mutations of residues that are involved in cholesterol binding will make CXCR4 and CCR5 insensitive to membrane cholesterol content. Cholesterol‐binding sites in HIV coreceptors are potential targets for steroid drugs that bind to CXCR4 and CCR5 with higher binding affinity than cholesterol, but do not stabilize the native conformation of these proteins. Proteins 2013. © 2012 Wiley Periodicals, Inc.