Woolley Michael J, Simms John, Uddin Sifat, Poyner David R, Conner Alex C
College of Medical and Dental Sciences, University of Birmingham , Edgbaston, Birmingham B15 2TT, U.K.
School of Life and Health Sciences, Aston University , Aston Triangle, Birmingham B4 7ET, U.K.
Biochemistry. 2017 Aug 1;56(30):3877-3880. doi: 10.1021/acs.biochem.7b00077. Epub 2017 Jul 18.
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 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.
G蛋白偶联受体（GPCR）家族的第二个细胞外环（ECL2）对于配体相互作用和药物发现至关重要。B族心脏保护降钙素基因相关肽（CGRP）受体的ECL2是细胞信号传导所必需的。B族GPCR配体有两个区域；N端介导受体激活，其余部分赋予高亲和力结合。通过比较CGRP受体ECL2多个点突变处CGRP的拮抗作用，我们发现ECL2可能促进与CGRP多达18个N端残基的相互作用。这对于理解B族GPCR激活以及CGRP受体的药物设计具有重要意义。
