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. and Conner, Alex 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), pp. 3877-3880.

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.

Publication DOI: https://doi.org/10.1021/acs.biochem.7b00077
Divisions: Life & Health Sciences > Biosciences
Life & Health Sciences > Pharmacy
Life & Health Sciences
Additional Information: 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).
Uncontrolled Keywords: Biochemistry
Full Text Link:
Related URLs: http://www.scop ... tnerID=8YFLogxK (Scopus URL)
Published Date: 2017-08
Authors: Woolley, Michael J.
Simms, John
Uddin, Sifat
Poyner, David R. ( 0000-0003-1590-112X)
Conner, Alex C.

Download

[img]

Version: Accepted Version

| Preview

Export / Share Citation


Statistics

Additional statistics for this record