MODELING THE STRUCTURE OF THE CALCITONIN-GENE-RELATED PEPTIDE

The calcitonin gene-related peptide (CGRP) is a 37 residue neuropeptid e which causes vasodilatation, increases heart rate and inhibits bone resorption. These effects make it an interesting lead for drug discove ry. We have combined current structural and biological information to model the structure of hCGRP-beta to be used as a basis for the ration al design of novel analogues. Distinct regions of CGRP have been shown to be responsible for the activity of the whole molecule. Thus, the s tructure of the peptide was modelled in four parts which were finally combined. A random search of conformational space was performed for th e fragments CGRP1-8 and CGRP30-37 which have been shown to be central for receptor activation and binding, respectively. Five low-energy hCG RP-beta structures were obtained from modelled fragments by molecular dynamics. The relevance of the approach was verified by comparing the models with NMR structures of CGRP and calcitonin. The models obtained for the N- and C-terminal fragments should enable the design of novel agonists and antagonists of the CGRP receptor, respectively. Models o f the whole molecule may be used in the design of peptides with shorte ned spacers between the receptor-bound regions. The approach described is applicable to several related peptide hormones, like growth hormon e-releasing hormone and secretin.