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 (CGRP_8-37): 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

^*Corresponding author for this work

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

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 CGRP_8-37 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 - Aug 2017

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).

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10.1021/acs.biochem.7b00077

Relative antagonism of mutants of the CGRP receptor ECL2
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
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@article{dfc87a3130df412c8e82ebbbbe221491,

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.}",

note = "This document is the Accepted Manuscript version of a Published Work that appeared in final form in Biochemistry, copyright {\textcopyright} 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).",

year = "2017",

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

language = "English",

volume = "56",

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journal = "Biochemistry",

issn = "0006-2960",

publisher = "American Chemical Society",

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Relative antagonism of mutants of the CGRP receptor extracellular loop 2 domain (ECL2) using a truncated competitive antagonist (CGRP_8-37): 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, 08.2017, p. 3877-3880.

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

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AU - Conner, Alex C.

N1 - 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).

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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.

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