Elucidation of Signaling Mechanism of ANP Receptor by X-Ray Crystallography

Abstract

Atrial natriuretic peptide (ANP) plays a major role in the regulation of blood pressure and volume regulation. The actions of ANP are mediated by a ANP receptor, a single span transmembrane receptor carrying intrinsic guanylate cyclase activity. The ANP receptor consists of a glycosylated extracellular ANP-binging domain and an intracellular domains including a guanylyl cyclase catalytic domain, and acts as a homodimer. The receptor is a member of a family of GCase-coupled receptors that share a similar overall molecular configuration and, presumably, a common signal transduction mechanism. However, the mechanism remains largely unknown. Here, we have solved crystal structures of extracellular ANP-binging domain in complex with three ligands (ANP, ANP lacking its C-terminus region and Dendroaspis natriuretic peptide (DNP), isolated from the venom of the green Mamba snake Dendroaspis angusticeps). High resolution structure allows us to build the bound ligands precisely, including water molecules. Plausible mechanisms of ligand recognition and transmembrane signal transduction mechanism, and insight from the structures will be discussed.