The Structure of the CGRP and Related Receptors.
The Structure of the CGRP and Related Receptors.
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DOI：
10.1007/164_2018_132
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发表时间：
2018-05
影响因子：
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通讯作者：
J. Simms;S. Routledge;Romez Uddin;D. Poyner
中科院分区：
文献类型：
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作者：
J. Simms;S. Routledge;Romez Uddin;D. Poyner
典型的CGRP受体是降钙素受体样受体(CLR)、B家族G蛋白偶联受体(GPCR)和受体活性修饰蛋白1(RAMP1)的复合体。第三种蛋白质，受体成分蛋白(RCP)是与Gs偶联所必需的。CGRP可以与其他RAMP受体复合体相互作用，特别是降钙素受体(CTR)和RAMP1之间形成的AMY1受体。CGRP27-37[D31，P34，F35]与CLR和RAMP1的胞外区(ECD)结合的晶体结构表明，CGRP的极端C端酰胺与RAMP1的W84相互作用，而其余类似物与CLR相互作用。与CLR/RAMP2 ECD结合的肾上腺髓质素结合片段的晶体结构比较证实了配体C末端和RAMP之间的相互作用在确定药理特异性方面的重要性，尽管RAMP可能也具有变构作用。降钙素与Gs相关的全长CTR结合的冷冻电子显微镜结构为完整受体的结构提供了重要线索，并表明CGRP的N端与CLR的TM5上的His5.40b接触。然而，目前还不知道坡道如何与任何GPCR的TM束相互作用。主要的挑战仍然是理解ECD和TM结构域如何共同作用来确定配体的特异性，以及G蛋白如何影响这一点和RCP的作用。变构机制似乎特别重要，受体的动力学也是如此。
The canonical CGRP receptor is a complex between calcitonin receptor-like receptor (CLR), a family B G-protein-coupled receptor (GPCR) and receptor activity-modifying protein 1 (RAMP1). A third protein, receptor component protein (RCP) is needed for coupling to Gs. CGRP can interact with other RAMP–receptor complexes, particularly the AMY1 receptor formed between the calcitonin receptor (CTR) and RAMP1. Crystal structures are available for the binding of CGRP27–37[D31,P34,F35] to the extracellular domain (ECD) of CLR and RAMP1; these show that extreme C-terminal amide of CGRP interacts with W84 of RAMP1 but the rest of the analogue interacts with CLR. Comparison with the crystal structure of a fragment of the allied peptide adrenomedullin bound to the ECD of CLR/RAMP2 confirms the importance of the interaction of the ligand C-terminus and the RAMP in determining pharmacology specificity, although the RAMPs probably also have allosteric actions. A cryo-electron microscope structure of calcitonin bound to the full-length CTR associated with Gs gives important clues as to the structure of the complete receptor and suggests that the N-terminus of CGRP makes contact with His5.40b, high on TM5 of CLR. However, it is currently not known how the RAMPs interact with the TM bundle of any GPCR. Major challenges remain in understanding how the ECD and TM domains work together to determine ligand specificity, and how G-proteins influence this and the role of RCP. It seems likely that allosteric mechanisms are particularly important as are the dynamics of the receptors.