Modelling the structure of the calcitonin gene-related peptide.
The calcitonin gene-related peptide (CGRP) is a 37 residue neuropeptide which causes vasodilatation, increases heart rate and inhibits bone resorption. These effects make it an interesting lead for drug discovery. We have combined current structural and biological information to model the structure of hCGRP-beta to be used as a basis for the rational design of novel analogues. Distinct regions of CGRP have been shown to be responsible for the activity of the whole molecule. Thus, the structure of the peptide was modelled in four parts which were finally combined. A random search of conformational space was performed for the fragments CGRP1-8 and CGRP30-37 which have been shown to be central for receptor activation and binding, respectively. Five low-energy hCGRP-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 of the whole molecule may be used in the design of peptides with shortened spacers between the receptor-bound regions. The approach described is applicable to several related peptide hormones, like growth hormone-releasing hormone and secretin.
Hakala
J M
JM
Turku Centre for Biotechnology, University of Turku, Finland.
Vihinen
M
M
D000595:Amino Acid Sequence; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000737:chemistry* / Q000235:genetics; D006801:Humans; D006860:Hydrogen Bonding; D008958:Models, Molecular; D008969:Molecular Sequence Data; D015394:Molecular Structure; D011487:Protein Conformation; D015202:Protein Engineering; D017433:Protein Structure, Secondary; D017386:Sequence Homology, Amino Acid; D013816:Thermodynamics
D015740:Calcitonin Gene-Related Peptide