Loughborough University
Leicestershire, UK
LE11 3TU
+44 (0)1509 263171
Loughborough University

Loughborough University Institutional Repository

Please use this identifier to cite or link to this item: https://dspace.lboro.ac.uk/2134/14779

Title: Residues within the transmembrane domain of the glucagon-like peptide-1 receptor involved in ligand binding and receptor activation: modelling the ligand-bound receptor
Authors: Coopman, Karen
Wallis, R.
Robb, G.
Brown, A.J.H.
Wilkinson, Graeme F.
Timms, D.
Willars, Gary B.
Keywords: GLP-1 receptor
Ligand binding
Receptor activation
Structural model
Family B GPCR
Issue Date: 2011
Publisher: © Endocrine Society
Citation: COOPMAN, K. ... et al., 2011. Residues within the transmembrane domain of the glucagon-like peptide-1 receptor involved in ligand binding and receptor activation: modelling the ligand-bound receptor. Molecular Endocrinology, 25 (10), pp. 1804 - 1818.
Abstract: The C-terminal regions of glucagon-like peptide-1 (GLP-1) bind to the N terminus of the GLP-1 receptor (GLP-1R), facilitating interaction of the ligand N terminus with the receptor transmembrane domain. In contrast, the agonist exendin-4 relies less on the transmembrane domain, and truncated antagonist analogs (e.g. exendin 9–39) may interact solely with the receptor N terminus. Here we used mutagenesis to explore the role of residues highly conserved in the predicted transmembrane helices of mammalian GLP-1Rs and conserved in family B G protein coupled receptors in ligand binding and GLP-1R activation. By iteration using information from the mutagenesis, along with the available crystal structure of the receptor N terminus and a model of the active opsin transmembrane domain, we developed a structural receptor model with GLP-1 bound and used this to better understand consequences of mutations. Mutation at Y152 [transmembrane helix (TM) 1], R190 (TM2), Y235 (TM3), H363 (TM6), and E364 (TM6) produced similar reductions in affinity for GLP-1 and exendin 9–39. In contrast, other mutations either preferentially [K197 (TM2), Q234 (TM3), and W284 (extracellular loop 2)] or solely [D198 (TM2) and R310 (TM5)] reduced GLP-1 affinity. Reduced agonist affinity was always associated with reduced potency. However, reductions in potency exceeded reductions in agonist affinity for K197A, W284A, and R310A, while H363A was uncoupled from cAMP generation, highlighting critical roles of these residues in translating binding to activation. Data show important roles in ligand binding and receptor activation of conserved residues within the transmembrane domain of the GLP-1R. The receptor structural model provides insight into the roles of these residues.
Description: This article was published in the journal [© Endocrine Society] and the definitive version is available at: http://dx.doi.org/10.1210/me.2011-1160
Version: Accepted for publication
DOI: 10.1210/me.2011-1160
URI: https://dspace.lboro.ac.uk/2134/14779
Publisher Link: http://dx.doi.org/10.1210/me.2011-1160
ISSN: 0888-8809
Appears in Collections:Published Articles (Chemical Engineering)

Files associated with this item:

File Description SizeFormat
Coopman et al 2011 final for IR.pdfAccepted version598.28 kBAdobe PDFView/Open


SFX Query

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.