3 years ago

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

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

Publisher URL: http://dx.doi.org/10.1021/acs.biochem.7b00077

DOI: 10.1021/acs.biochem.7b00077

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