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

doi:10.1021/acs.biochem.7b00077

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 journal › Article › peer-review

3 Citations (Scopus)

173 Downloads (Pure)

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 language	English
Pages (from-to)	3877-3880
Number of pages	4
Journal	Biochemistry
Volume	56
Issue number	30
Early online date	10 Jul 2017
DOIs	https://doi.org/10.1021/acs.biochem.7b00077
Publication status	Published - 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

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10.1021/acs.biochem.7b00077

Woolley_et_al_Relative_antagonism_of_mutants_Biochemistry_2017
Checked for eligibility: 11/10/2017 This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemsitry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://pubs.acs.org/doi/abs/10.1021/acs.biochem.7b00077
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The second extracellular loop of the CGRP receptor: A docking site for vasoprotective ligands
Conner, A.
British Heart Foundation
1/01/14 → 31/12/16
Project: Research

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Woolley, M. J., Simms, J., Uddin, S., Poyner, D. R., & Conner, A. C. (2017). 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. Biochemistry, 56(30), 3877-3880. Advance online publication. https://doi.org/10.1021/acs.biochem.7b00077

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title = "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",

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.",

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",

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doi = "10.1021/acs.biochem.7b00077",

language = "English",

volume = "56",

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

Research output: Contribution to journal › Article › peer-review

TY - JOUR

T1 - Relative Antagonism of Mutants of the CGRP Receptor Extracellular Loop 2 Domain (ECL2) Using a Truncated Competitive Antagonist (CGRP8-37)

T2 - Evidence for the Dual Involvement of ECL2 in the Two-Domain Binding Model

AU - Woolley, Michael J

AU - Simms, John

AU - Uddin, Sifat

AU - Poyner, David R

AU - Conner, Alex C

PY - 2017/8/1

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N2 - 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.

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

U2 - 10.1021/acs.biochem.7b00077

DO - 10.1021/acs.biochem.7b00077

M3 - Article

C2 - 28691801

SN - 0006-2960

VL - 56

SP - 3877

EP - 3880

JO - Biochemistry

JF - Biochemistry

IS - 30

ER -

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

Abstract

Keywords

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The second extracellular loop of the CGRP receptor: A docking site for vasoprotective ligands

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