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MODELING THE STRUCTURE OF THE CALCITONIN-GENE-RELATED PEPTIDE

HAKALA, JML and Vihinen, Mauno LU (1994) In Protein Engineering 7(9). p.1069-1075
Abstract
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,... (More)
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. (Less)
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author
publishing date
type
Contribution to journal
publication status
published
subject
keywords
CALCITONIN, GENE-RELATED, MODELING, PEPTIDE, STRUCTURE
in
Protein Engineering
volume
7
issue
9
pages
1069 - 1075
publisher
Oxford University Press
external identifiers
  • wos:A1994PG50700002
  • scopus:0028168137
ISSN
1460-213X
DOI
10.1093/protein/7.9.1069
language
English
LU publication?
no
id
f2765419-3f6b-439c-ac17-a0f93156e248 (old id 3853361)
date added to LUP
2013-06-28 14:48:38
date last changed
2017-01-01 04:26:50
@article{f2765419-3f6b-439c-ac17-a0f93156e248,
  abstract     = {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.},
  author       = {HAKALA, JML and Vihinen, Mauno},
  issn         = {1460-213X},
  keyword      = {CALCITONIN,GENE-RELATED,MODELING,PEPTIDE,STRUCTURE},
  language     = {eng},
  number       = {9},
  pages        = {1069--1075},
  publisher    = {Oxford University Press},
  series       = {Protein Engineering},
  title        = {MODELING THE STRUCTURE OF THE CALCITONIN-GENE-RELATED PEPTIDE},
  url          = {http://dx.doi.org/10.1093/protein/7.9.1069},
  volume       = {7},
  year         = {1994},
}