Relative Antagonism of Mutants of the CGRP Receptor Extracellular Loop 2 Domain (ECL2) Using a Truncated Competitive Antagonist (CGRP8-37): Evidence for the Dual Involvement of ECL2 in the Two-Domain Binding Model

Research output: Contribution to journalArticle

Authors

  • Mike Woolley
  • John Simms
  • Sifat Uddin
  • David R Poyner
  • Alex C Conner

Colleges, School and Institutes

External organisations

  • College of Medical and Dental Sciences, University of Birmingham , Edgbaston, Birmingham B15 2TT, U.K.
  • Aston University

Abstract

The second extracellular loop (ECL2) of the G protein-coupled receptor (GPCR) family is important for ligand interaction and drug discovery. ECL2 of the family B cardioprotective calcitonin gene-related peptide (CGRP) receptor is required for cell signaling. Family B GPCR ligands have two regions; the N-terminus mediates receptor activation, and the remainder confers high-affinity binding. Comparing antagonism of CGRP8-37 at a number of point mutations of ECL2 of the CGRP receptor, we show that the ECL2 potentially facilitates interaction with up to the 18 N-terminal residues of CGRP. This has implications for understanding family B GPCR activation and for drug design at the CGRP receptor.

Details

Original languageEnglish
Pages (from-to)3877-3880
Number of pages4
JournalBiochemistry
Volume56
Issue number30
Early online date10 Jul 2017
Publication statusPublished - 1 Aug 2017

Keywords

  • Amino Acid Substitution, Animals, Binding Sites, Binding, Competitive, COS Cells, Calcitonin Gene-Related Peptide, Calcitonin Receptor-Like Protein, Cercopithecus aethiops, Kinetics, Ligands, Miotics, Models, Molecular, Peptide Fragments, Point Mutation, Protein Conformation, Protein Interaction Domains and Motifs, Protein Interaction Mapping, Protein Multimerization, Receptor Activity-Modifying Protein 1, Receptors, Calcitonin Gene-Related Peptide, Recombinant Proteins, Signal Transduction, Structural Homology, Protein, Comparative Study, Journal Article