期刊
ACS PHARMACOLOGY & TRANSLATIONAL SCIENCE
卷 3, 期 2, 页码 263-284出版社
AMER CHEMICAL SOC
DOI: 10.1021/acsptsci.9b00080
关键词
cryo-electron microscopy; adrenomedullin; calcitonin gene-related peptide; G protein-coupled receptor; receptor activity-modifying protein; allosteric modulation; receptor structure-function
资金
- Monash University Ramaciotti Centre for Cryo-Electron Microscopy
- National Health and Medical Research Council of Australia (NHMRC) [1120919, 1159006]
- NHMRC program grant [1150083]
- Japan Society for the Promotion of Science (JSPS, KAKENHI) [18H06043]
- Japan Science and Technology Agency (JST, PRESTO) [18069571]
- Japan Science and Technology Agency (Biotechnology and Biological Sciences Research Council, UK (BBSRC)) [BB/M006883]
- Monash MASSIVE high-performance computing facility
- National Health and Medical Research Council of Australia [1150083, 1120919, 1159006] Funding Source: NHMRC
- Grants-in-Aid for Scientific Research [18H06043] Funding Source: KAKEN
Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) receptors are critically important for metabolism, vascular tone, and inflammatory response. AM receptors are also required for normal lymphatic and blood vascular development and angiogenesis. They play a pivotal role in embryo implantation and fertility and can provide protection against hypoxic and oxidative stress. CGRP and AM receptors are heterodimers of the calcitonin receptor-like receptor (CLR) and receptor activity-modifying protein 1 (RAMP1) (CGRPR), as well as RAMP2 or RAMP3 (AM(1)R and AM(2)R, respectively). However, the mechanistic basis for RAMP modulation of CLR phenotype is unclear. In this study, we report the cryo-EM structure of the AM(1)R in complex with AM and Gs at a global resolution of 3.0 angstrom, and structures of the AM(2)R in complex with either AM or intermedin/adrenomedullin 2 (AM2) and Gs at 2.4 and 2.3 angstrom, respectively. The structures reveal distinctions in the primary orientation of the extracellular domains (ECDs) relative to the receptor core and distinct positioning of extracellular loop 3 (ECL3) that are receptor-dependent. Analysis of dynamic data present in the cryo-EM micrographs revealed additional distinctions in the extent of mobility of the ECDs. Chimeric exchange of the linker region of the RAMPs connecting the TM helix and the ECD supports a role for this segment in controlling receptor phenotype. Moreover, a subset of the motions of the ECD appeared coordinated with motions of the G protein relative to the receptor core, suggesting that receptor ECD dynamics could influence G protein interactions. This work provides fundamental advances in our understanding of GPCR function and how this can be allosterically modulated by accessory proteins.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据