title: Inhibition of G-protein-coupled receptor function by disruption of transmembrane domain interactions.
abstract: 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 microM. 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.
authors.affiliation: Molecular Aspects of Drug Design Section, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Maryland 21702, USA. Tarasova@ncifcrf.gov
authors.forename: N I
authors.initials: NI
authors.lastname: Tarasova
authors.forename: W G
authors.initials: WG
authors.lastname: Rice
authors.forename: C J
authors.initials: CJ
authors.lastname: Michejda
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D065100:CCR5 Receptor Antagonists; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D002470:Cell Survival; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D015497:HIV-1 / Q000254:growth & development / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology; D017434:Protein Structure, Tertiary / Q000502:physiology; D051381:Rats; D019713:Receptors, CCR5 / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects
chemical_list: D065100:CCR5 Receptor Antagonists; D010455:Peptides; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins; D002118:Calcium