This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Atrial natriuretic peptide (ANP) is a cardiac hormone that stimulates salt excretion and dilates blood vessels. ANP plays a major role in blood pressure and salt-fluid volume regulation, and anomaly in its activities may cause heart failure, hypertension, and other cardiovascular diseases. ANP activities are mediated by a specific cell membrane receptor coupled to its intrinsic guanylate cyclase (GCase) activity. The receptor functions as a dimer of a single-span transmembrane protein, each consisting of an extracellular ANP-binding domain and an intracellular GCase catalytic domain. ANP binding to the extracellular domain activates GCase catalysis by an yet unknown mechanism.
Our aims are to determine the structure of ANP receptor and to elucidate the mechanisms of receptor-hormone binding and transmembrane signaling. During the past year, we determined the crystal structure of the extracellular domain of the receptor (ANPR) in complex with the hormone ANP. By the structural comparison with the apo-receptor structure that we determined previously, we have identified a structural basis for ANP receptor signaling. We have found a unique hormone-induced rotation motion of the two juxtamembrane domains in the receptor dimmer that apparently initiates transmembrane signal transduction. Additionally, w have determine the crystal structure of the ANPR containing a non-covalently associated bromide ion (instead of chloride ion in the native receptor) (manuscript in preparation). We also have obtained preliminary structures of two constitutively active ANPR mutants. These studies will provide better understanding of the mechanism of ANP and ANP interaction, receptor activation, and regulation. Such knowledge will lead to more accurate diagnosis methods and effective treatments for cardiovascular diseases. These studies will also facilitate development of drugs targeted at the ANP receptor via structure-based drug design. Those drugs will be useful in treating heart failure, hypertension, and other cardiovascular diseases.An
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