Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions

被引:79
作者
Tarasova, NI
Rice, WG
Michejda, CJ
机构
[1] NCI, Frederick Canc Res & Dev Ctr, ABL Basic Res Program, Mol Aspects Drug Design Sect, Frederick, MD 21702 USA
[2] NCI, Frederick Canc Res & Dev Ctr, Lab Antiviral Drug Mechanisms, Frederick, MD 21702 USA
关键词
D O I
10.1074/jbc.274.49.34911
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
G-protein-coupled receptors (GPCR) represent a superfamily of proteins that mediate the function of neurotransmitters and peptide hormones and are involved in viral entry and perception of light, smell, and taste. GPCRs are characterized by the presence of seven transmembrane domains (TMs). We demonstrate here that structural analogs of individual TMs of GPCRs can serve as potent and specific receptor antagonists. Peptides derived from the transmembrane regions of CXCR4 and CCR5 chemokine receptors specifically inhibited receptor signaling and the in vitro replication of human immunodeficiency virus-1 (HIV-1) at concentrations as low as 0.2 mu M. Similarly, peptides mimicking the TMs of cholecystokinin receptor A, were found to abolish ligand binding and signaling through the receptor. Negative charges positioned at the extracellular termini of peptide antagonists appeared to be important for correct spontaneous insertion of the compounds into the cell membrane and for their activity. Targeting of the specific interactions between transmembrane domains of GPCRs is suggested as a general sequence-based method to disrupt receptor function for application in drug design and for structure-function studies of the receptors.
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页码:34911 / 34915
页数:5
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