Insights into the molecular evolution of oxytocin receptor ligand binding

Koehbach, Johannes, Stockner, Thomas, Bergmayr, Christian, Muttenthaler, Markus and Gruber, Christian W. (2013) Insights into the molecular evolution of oxytocin receptor ligand binding. Biochemical Society Transactions, 41 1: 197-204. doi:10.1042/BST20120256


Author Koehbach, Johannes
Stockner, Thomas
Bergmayr, Christian
Muttenthaler, Markus
Gruber, Christian W.
Title Insights into the molecular evolution of oxytocin receptor ligand binding
Journal name Biochemical Society Transactions   Check publisher's open access policy
ISSN 0300-5127
1470-8752
Publication date 2013-02-01
Year available 2013
Sub-type Article (original research)
DOI 10.1042/BST20120256
Open Access Status DOI
Volume 41
Issue 1
Start page 197
End page 204
Total pages 8
Place of publication London, United Kingdom
Publisher Portland Press
Language eng
Abstract The design and development of selective ligands for the human OT (oxytocin) and AVP (arginine vasopressin) receptors is a big challenge since the different receptor subtypes and their native peptide ligands display great similarity. Detailed understanding of the mechanism of OT's interaction with its receptor is important and may assist in the ligand- or structure-based design of selective and potent ligands. In the present article, we compared 69 OT- and OT-like receptor sequences with regards to their molecular evolution and diversity, utilized an in silico approach to map the common ligand interaction sites of recently published G-protein-coupled receptor structures to a model of the human OTR (OT receptor) and compared these interacting residues within a selection of different OTR sequences. Our analysis suggests the existence of a binding site for OT peptides within the common transmembrane core region of the receptor, but it appears extremely difficult to identify receptor or ligand residues that could explain the selectivity of OT to its receptors. We remain confident that the presented evolutionary overview and modelling approach will aid interpretation of forthcoming OTR crystal structures.
Formatted abstract
The design and development of selective ligands for the human OT (oxytocin) and AVP (arginine vasopressin) receptors is a big challenge since the different receptor subtypes and their native peptide ligands display great similarity. Detailed understanding of the mechanism of OT's interaction with its receptor is important and may assist in the ligand- or structure-based design of selective and potent ligands. In the present article, we compared 69 OT- and OT-like receptor sequences with regards to their molecular evolution and diversity, utilized an in silico approach to map the common ligand interaction sites of recently published G-proteincoupled receptor structures to a model of the human OTR (OT receptor) and compared these interacting residues within a selection of different OTR sequences. Our analysis suggests the existence of a binding site for OT peptides within the common transmembrane core region of the receptor, but it appears extremely difficult to identify receptor or ligand residues that could explain the selectivity of OT to its receptors. We remain confident that the presented evolutionary overview and modelling approach will aid interpretation of forthcoming OTR crystal structures.
Keyword Arginine vasopressin
Binding
GPCR (G-protein-coupled receptor)
Homology model
OT (oxytocin)
Vasotocin
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID P22889-B11
254897
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Biomedical Sciences Publications
 
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