Structural characterization of peptide hormone/receptor interactions by NMR spectroscopy.
The structural characterization of peptide hormones and their interaction with G-protein (guanine nucleotide-binding regulatory protein) coupled receptors by high-resolution nmr is described. The general approaches utilized can be categorized into three different classes based on their target: the ligand, the receptor, and the ligand/receptor complex. Examples of these different approaches, aimed at facilitating the rational design of peptides and peptidomimetics with improved pharmacological profiles, based on work carried out in our own laboratory, are given. In the ligand-based approach, the high-resolution structures of bradykinin analogues allowing for the development of a structure-activity relationship for activation of the B1 receptor are described. Studies targeting the receptor are to a large extent theoretical, based on computational molecular modeling. However, experimentally based structural features provided by high-resolution nmr can be used to great advantage, providing insight into the mechanism of receptor function, as illustrated here with results from parathyroid hormone. A similar combination of theoretical methods, supplemented by high-resolution structures from nmr has been utilized to probe the formation and stabilization of the ligand/receptor complex both for parathyroid hormone and cholecystokinin. In each of these three approaches, the importance of well-designed peptide mimetics and accurate structural analysis by high-resolution nmr, will be highlighted.
Pellegrini
M
M
Department of Molecular Pharmacology, Physiology & Biotechnology, Division of Biology and Medicine, Brown University, Providence, RI 02912, USA.
Mierke
D F
DF
D000595:Amino Acid Sequence; D019204:GTP-Binding Proteins / Q000378:metabolism; D006728:Hormones / Q000737:chemistry* / Q000378:metabolism; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D011487:Protein Conformation; D018016:Receptors, Parathyroid Hormone / Q000737:chemistry / Q000378:metabolism; D018000:Receptors, Peptide / Q000737:chemistry* / Q000378:metabolism
D006728:Hormones; D008024:Ligands; D018016:Receptors, Parathyroid Hormone; D018000:Receptors, Peptide; D019204:GTP-Binding Proteins