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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/3853361
- author
- HAKALA, JML
and Vihinen, Mauno
LU
- publishing date
- 1994
- 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
- 2016-04-01 11:41:26
- date last changed
- 2021-01-03 06:57:05
@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}},
keywords = {{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}},
doi = {{10.1093/protein/7.9.1069}},
volume = {{7}},
year = {{1994}},
}