Peptide hormone binding to G-protein-coupled receptors: Structural characterization via NMR techniques

G-protein-coupled receptors (GPCRs) allow cells to respond to calcium, horm ones, and neurotransmitters. Not surprisingly they currently make up the la rgest family of validated drug targets. Rational drug design for molecular regulators targeting GPCRs has been limited to theoretical-based computatio nal approaches. X-ray crystallography of intact GPCRs has provided the topo logical orientation of the seven transmembrane helices, but limited structu ral information of the extracellular and intracellular loops and protein te rmini. In this review we detail an NMR-based approach which provides the hi gh-resolution structural features on the extracellular domains of GPCRs and the ligand/receptor complexes formed upon titration of the peptide hormone . The results provide important contact points and a high-resolution descri ption of the ligand/receptor interactions, which may be useful for the rati onal design of therapeutic agents targeting GPCRs. Recent results from our investigation of the cholecystokinin peptide hormone system arc used to hig hlight this approach. (C) 2001 John Wiley & Sons.