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

Fingerprint

Calcitonin Gene-Related Peptide Receptors
G-Protein-Coupled Receptors
CCR10 Receptors
Chemical activation
Cell signaling
Ligands
Calcitonin Gene-Related Peptide
Drug Design
Drug Discovery
Point Mutation
Pharmaceutical Preparations
calcitonin gene-related peptide (8-37)

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

Cite this

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

In: Biochemistry, Vol. 56, No. 30, 01.08.2017, p. 3877-3880.

Research output: Contribution to journalArticle

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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.",
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AU - Woolley, Michael J

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AU - Uddin, Sifat

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AU - Conner, Alex C

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AB - 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.

KW - Amino Acid Substitution

KW - Animals

KW - Binding Sites

KW - Binding, Competitive

KW - COS Cells

KW - Calcitonin Gene-Related Peptide

KW - Calcitonin Receptor-Like Protein

KW - Cercopithecus aethiops

KW - Kinetics

KW - Ligands

KW - Miotics

KW - Models, Molecular

KW - Peptide Fragments

KW - Point Mutation

KW - Protein Conformation

KW - Protein Interaction Domains and Motifs

KW - Protein Interaction Mapping

KW - Protein Multimerization

KW - Receptor Activity-Modifying Protein 1

KW - Receptors, Calcitonin Gene-Related Peptide

KW - Recombinant Proteins

KW - Signal Transduction

KW - Structural Homology, Protein

KW - Comparative Study

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

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