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

G-protein-coupled receptors (GPCR) represent a superfamily of proteins that mediate the function of neurotransmitters and peptide hormones and are inv olved in viral entry and perception of light, smell, and taste. GPCRs are c haracterized by the presence of seven transmembrane domains (TMs). We demon strate here that structural analogs of individual TMs of GPCRs can serve as potent and specific receptor antagonists. Peptides derived from the transm embrane regions of CXCR4 and CCR5 chemokine receptors specifically inhibite d 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 liga nd binding and signaling through the receptor. Negative charges positioned at the extracellular termini of peptide antagonists appeared to be importan t for correct spontaneous insertion of the compounds into the cell membrane and for their activity. Targeting of the specific interactions between tra nsmembrane domains of GPCRs is suggested as a general sequence-based method to disrupt receptor function for application in drug design and for struct ure-function studies of the receptors.