Exploring Ligand Binding to Calcitonin Gene-Related Peptide Receptors.
CGRP
CGRPR
GPCR
binding
molecular dynamics
supervised molecular dynamics
telcagepant
Journal
Frontiers in molecular biosciences
ISSN: 2296-889X
Titre abrégé: Front Mol Biosci
Pays: Switzerland
ID NLM: 101653173
Informations de publication
Date de publication:
2021
2021
Historique:
received:
04
06
2021
accepted:
13
08
2021
entrez:
13
9
2021
pubmed:
14
9
2021
medline:
14
9
2021
Statut:
epublish
Résumé
Class B1 G protein-coupled receptors (GPCRs) are important targets for many diseases, including cancer, diabetes, and heart disease. All the approved drugs for this receptor family are peptides that mimic the endogenous activating hormones. An understanding of how agonists bind and activate class B1 GPCRs is fundamental for the development of therapeutic small molecules. We combined supervised molecular dynamics (SuMD) and classic molecular dynamics (cMD) simulations to study the binding of the calcitonin gene-related peptide (CGRP) to the CGRP receptor (CGRPR). We also evaluated the association and dissociation of the antagonist telcagepant from the extracellular domain (ECD) of CGRPR and the water network perturbation upon binding. This study, which represents the first example of dynamic docking of a class B1 GPCR peptide, delivers insights on several aspects of ligand binding to CGRPR, expanding understanding of the role of the ECD and the receptor-activity modifying protein 1 (RAMP1) on agonist selectivity.
Identifiants
pubmed: 34513925
doi: 10.3389/fmolb.2021.720561
pii: 720561
pmc: PMC8427520
doi:
Types de publication
Journal Article
Langues
eng
Pagination
720561Subventions
Organisme : Biotechnology and Biological Sciences Research Council
ID : BB/M006883/1
Pays : United Kingdom
Informations de copyright
Copyright © 2021 Deganutti, Atanasio, Rujan, Sexton, Wootten and Reynolds.
Déclaration de conflit d'intérêts
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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