Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK.
J R Soc Interface. 2013 Sep 18;10(88):20130589. doi: 10.1098/rsif.2013.0589. Print 2013 Nov 6.
The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.
降钙素基因相关肽 (CGRP) 受体是降钙素受体样受体 (CLR) 的复合物，CLR 是 B 族家族 G 蛋白偶联受体 (GPCR) 和受体活性修饰蛋白 1。使用突变和建模相结合的方法研究了 CLR 的第二细胞外环 (ECL2) 在结合 CGRP 和与 Gs 偶联中的作用。对 CLR 的 271-294 位残基进行丙氨酸扫描表明，CGRP 产生 cAMP 的能力因 13 个残基的点突变而受损；其中大多数也损害了对肾上腺髓质素 (AM) 的反应。这些数据用于选择可能的 ECL2 建模构象，这些构象涉及激动剂结合，从而确定肽和受体之间的可能接触。讨论了最可能的结构对受体激活的影响。
