STRUCTURE OF HUMAN CALCITONIN-GENE-RELATED PEPTIDE (HCGRP) AND OF ITSANTAGONIST HCGRP-8-37 AS DETERMINED BY NMR AND MOLECULAR MODELING

The solution structures of human calcitonin gene-related peptide (hCGR P, 37 residues) and of its antagonistic fragment hCGRP 8-37 have been determined by two-dimensional H-1 nuclear magnetic resonance (NMR) spe ctroscopy and molecular modeling. Analysis of the double quantum filte red correlation spectroscopy, total correlation spectroscopy and nucle ar Overhauser enhancement spectroscopy spectra led to a complete assig nment and to the identification of move than 350 intra- and interresid ue connectivities for each peptide. Molecular models were calculated b y molecular dynamics and energy minimization using distance constraint s. The structure of hCGRP is characterized by a rigid N-terminal disul fide-bonded loop followed by helix segments (Val(8)-Leu(16)), a gamma- turn (Ser(19)-Gly(21)) and several local hydrogen-bonded patterns. The structure of hCGRP 8-37 is less defined than the structure of hCGRP a nd no helix structure is present. Molecular models of both peptides ar e consistent with the NH temperative coefficients and secondary chemic al shifts of the ex-protons. Hydrogen bonding with the disulfide-bonde d ring appears to be critical for helix formation, both structural ele ments being essential formation agonistic activity.