Secretin receptors structural analysis as a potential drug target

Abstract

G protein-coupled receptors (GPCRs) are pharmacologically vital, due to their role in several diseased conditions like osteoporosis, obesity, cancer, neurodegeneration, diabetes, cardiovascular disease and even psychiatric disorders. The secretin receptor (SCTR), a class B GPCR, is involved in many physiological functions such as HCO3- release from pancreas, fatty acid absorption and water homeostasis, other studies also suggest that secretin may improve cardiac profile and it can also mediate insulin secretion upon its action on pancreatic beta cells. We have developed a 3D model of SCTR [1] and have successfully expressed and purified the N terminal extracellular domain of SCTR. In this study we aim to solve its structure. We are also interested in the structural changes occurred during the evolution of class B GPCRs and hence intend to develop 3D model of some Class B GPCRs from human, amphioxus and zebrafish. Unlike class A and class C GPCRs the class B GPCRs are known to have a long N terminal extracellular domain. Using SCTR as a model for class B GPCR, we recently reported that both the N and C terminal regions of the peptide ligand are essential for its binding to the receptor [1]. Furthermore it is well acknowledged that the peptide ligand binds to the N terminal domain. Aided by the recent finding of the endogenous agonistic mechanism of activation [2], we aim to use the information in developing a direct agonistic molecule for the receptor and also to study the mechanism of receptor activation. The receptor is known to be activated by the secretin peptide which has a short plasma half-life (4 min in man) and therefore, there is a need to develop non-peptide agonist and/or antagonist. We hypothesize that the binding site for an agonist to be within the TM region of receptor, while the antagonist binds to the N terminal domain. By utilizing the information produced by the solving the structure of N terminal domain, we aim to design a direct antagonist for SCTR which will possibly be of high pharmacological importance. We have also identified glycyrrhizic acid as an indirect agonist for SCTR capable of triggering the release of secretin peptide after i.p. injection of 10mg/kg/bw.