Structure of the dimerized hormone-binding domain of a guanylyl-cyclase-coupled receptor

The atrial natriuretic peptide (ANP) hormone is secreted by the heart in re sponse to an increase in blood pressure. ANP exhibits several potent anti-h ypertensive actions in the kidney, adrenal gland and vascular system. These actions are induced by hormone binding extracellularly to the ANPreceptor( 1), thereby activating its intracellular guanylyl cyclase domain for the pr oduction of cyclic GMP(2). Here we present the crystal structure of the gly cosylated dimerized hormone-binding domain of the ANP receptor at 2.0-Angst rom resolution. The monomer comprises two interconnected subdomains, each e ncompassing a central beta-sheet flanked by alpha-helices, and exhibits the type I periplasmic binding protein fold. Dimerization is mediated by the j uxtaposition of four parallel helices, arranged two by two, which brings th e two protruding carboxy termini into close relative proximity. From affini ty labelling and mutagenesis studies, the ANP-binding site maps to the side of the dimer crevice and extends to near the dimer interface. A conserved chloride-binding site is located in the membrane distal domain, and we foun d that hormone binding is chloride dependent. These studies suggest mechani sms for hormone activation and the allostery of the ANP receptor.