Modelling the structure of the calcitonin gene-related peptide

The calcitonin gene-related peptide (CGRP) is a 37 residue neuropeptidewhich causes vasodilatation, increases heart rate and inhibitsbone resorption. These effects make it an interesting lead fordrug discovery. We have combined current structural and biologicalinformation to model the structure of hCGRP-ß to beused as a basis for the rational design of novel analogues.Distinct regions of CGRP have been shown to be responsible forthe activity of the whole molecule. Thus, the structure of thepeptide was modelled in four parts which were finally combined.A random search of conformational space was performed for thefragments CGRP1–8 and CGRP30–37 which have beenshown to be central for receptor activation and binding, respectively.Five low-energy hCGRP-ß structures were obtained frommodelled fragments by molecular dynamics. The relevance of theapproach was verified by comparing the models with NMR structuresof CGRP and calcitonin. The models obtained for the N- and C-terminalfragments should enable the design of novel agonists and antagonistsof the CGRP receptor, respectively. Models of the whole moleculemay be used in the design of peptides with shortened spacersbetween the receptor-bound regions. The approach described isapplicable to several related peptide hormones, like growthhormone-releasing hormone and secretin.