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

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.

LanguageEnglish
Pages3877-3880
Number of pages4
JournalBiochemistry
Volume56
Issue number30
Early online date10 Jul 2017
DOIs
Publication statusPublished - Aug 2017

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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)

Bibliographical note

This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see http://dx.doi.org/10.1021/acs.biochem.7b00077

Funding: BHF (PG/12/59/29795); BBSRC (BB/M007529/1).

Cite this

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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.",
author = "Woolley, {Michael J.} and John Simms and Sifat Uddin and Poyner, {David R.} and Conner, {Alex C.}",
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T1 - Relative antagonism of mutants of the CGRP receptor extracellular loop 2 domain (ECL2) using a truncated competitive antagonist (CGRP8-37)

T2 - Biochemistry

AU - Woolley, Michael J.

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AU - Uddin, Sifat

AU - Poyner, David R.

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.

UR - http://pubs.acs.org/doi/abs/10.1021/acs.biochem.7b00077

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