SOLUTION CONFORMATION OF AN ATRIAL-NATRIURETIC-PEPTIDE VARIANT SELECTIVE FOR THE TYPE-A RECEPTOR

Two-dimensional NMR spectroscopy has been used to characterize the solution conformation of an atrial natriuretic peptide (ANP) variant which is selective for the human natriuretic peptide receptor A (NPR-A) relative to receptor C (NPR-C). The ANP mutant, containing six substitutions, has reduced flexibility in aqueous solution relative to wild-type ANP and allows the observation of sufficient NOE connectivities for structure determination by distance geometry and restrained molecular dynamics calculations. The solution conformation is reasonably well defined, having an average backbone atom rms deviation from the average coordinates of similar to 1.1 Angstrom for residues 7-27. The structure is consistent with available functional data and shows a spatial separation between known receptor binding determinants and residues found to be outside the hormone-receptor interface.