CHARACTERIZATION OF THE HORMONE-BINDING SITE OF NATRIURETIC PEPTIDE RECEPTOR-C

The hormone binding site of rat and human natriuretic peptide clearanc e receptor (NPR-C), a single transmembrane receptor, has been further refined by mutagenesis. In addition to residue 188 (rat Ala, human Ile ), which completely inverts the pharmacology of the rat and human rece ptors [Engel et al. (1994) J. Biol. Chem. 269, 17005-17008], we report a second key residue at position 205 (rat Tyr, human Asn) which modul ates affinity to a limited number of ligands. Orthologous mutation of both residues results in tighter binding for human and weaker binding for rat NPR-C, The ligand binding fold of the receptor is formed by at least the first half of the extracellular domain containing two intra molecular disulfide loops, with the two affinity-modulating residues 1 88 and 205 in the second loop.