biostudies-literatureWoolley MJBritish Heart FoundationMedical Research CouncilWellcome Trust20130589https://www.ebi.ac.uk/biostudies/studies/S-EPMC3785825biostudies-literatureUnknown10(88)The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely strJournal of the Royal Society, InterfaceThe role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach.PMC3785825PG/12/59/29795G1001812091496Karakullukcu ZGPoyner DRTaddese BHay DLReynolds CABarwell JSmith KJWoolley MJConner ACWatkins HAfalseThe role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach.The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely str2013-01-01T00:00:00Z2013 Nov2025-04-18T15:54:15.416Z2019-03-26T22:41:11ZS-EPMC37858252404787210.1098/rsif.2013.0589