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

Michael J Woolley, John Simms, Sifat Uddin, David R Poyner, Alex C Conner

Research output: Contribution to journalArticle

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)3877-3880
Number of pages4
JournalBiochemistry
Volume56
Issue number30
DOIs
Publication statusPublished - 1 Aug 2017
Externally publishedYes

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
  • Research Support, Non-U.S. Gov't

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