Structural insight into hormone recognition and transmembrane signaling by the atrial natriuretic peptide receptor
Atrial natriuretic peptide (ANP) is an endogenous and potent hypotensive hormone that elicits natriuretic, diuretic, vasorelaxant, and anti proliferative effects, which play a central role in the regulation of blood pressure and volume. To investigate the hormone binding and membrane signaling mechanisms mediated by the ANP receptor, we elucidated the crystal structures of the ANP receptor extracellular hormone binding domain (ANPR) complexed with full length ANP, truncated mutants of ANP, and dendroaspis natriuretic peptide (DNP) isolated from the venom of the green Mamba snake, Dendroaspis angusticeps. The bound peptides possessed pseudo two fold symmetry to which the tight coupling of the peptide to the receptor and guanylyl cyclase activity was attributed. The crystal structures and our results from kinetic experiments provide insight into the ligand recognition and transmembrane signaling mechanism of the ANP receptor. Our findings provide useful information that can be applied to drug discovery for heart failure therapies.