全长糖蛋白激素受体信号复合物的结构
Jia Duan1,2, Peiyu Xu1,2, Xi Cheng1
1The CAS Key Laboratory of Receptor Research and State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
Nature
|September 23, 2021
概括
对素化荷尔蒙-胆激素受体 (LHCGR) 激活的结构洞察力揭示了一个新的
科学领域:
- 结构生物学
- 内分泌学
- 分子药理学
背景情况:
- 化激素 (LH) 和胆管性腺激素 (CG) 是生殖的关键糖蛋白激素.
- 这些激素激活了G蛋白合受体 - - 黄蛋白激素受体 (LHCGR).
- LHCGR是治疗内分泌疾病的关键目标.
研究的目的:
- 阐明LH和CG激活LHCGR的结构机制.
- 了解保留链区域在受体信号传递中的作用.
- 为开发针对LHCGR的新药提供结构基础.
主要方法:
- 使用冷电子显微镜 (cryo-EM) 来确定LHCGR的四个不同的结构.
- 结构捕获了野生类型的LHCGR在非活跃和活跃状态,以及构成性活跃的突变物.
- 复杂的结构包括结合CG,Gs蛋白和一个全激动剂 (Org43553).
主要成果:
- 确定了受体激活的"推拉"机制,涉及激素结合和链动态.
- 在链环中保存的10-残留片段 (P10) 作为绑定的激动剂,驱动跨膜域的结构变化.
- 通过与P10片段相互作用,全性激素Org43553稳定了活性受体构成.
结论:
- 这些结构为理解糖蛋白激素受体信号提供了一个统一的模型.
- 这些发现为LHCGR激活和基调节提供了关键的见解.
- 这项工作为针对内分泌疾病的基于结构的药物发现奠定了基础.
相关概念视频
Assembly of Signaling Complexes
6.1K
Multiprotein signaling complexes are formed in a dynamic process involving protein-protein interactions at the cytoplasmic domain of transmembrane receptors or enzymatic and non-enzymatic proteins associated with the receptor. These complexes ensure the activation and propagation of intracellular signals that regulate cell functions.
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
Interaction domains in cell signaling
Interaction domains recognize exposed features of their binding partners containing post-translationally modified sequences,...
6.1K
Endocrine Signaling
65.6K
Endocrine cells produce hormones to communicate with remote target cells found in other organs. The hormone reaches these distant areas using the circulatory system. This exposes the whole organism to the hormone but only those cells expressing hormone receptors or target cells are affected. Thus, endocrine signaling induces slow responses from its target cells but these effects also last longer.
65.6K
Secondary Messengers in Hormone Action
3.5K
Water-soluble hormones cannot cross the plasma membrane, so they rely on protein receptors that span the membrane to trigger intracellular signaling pathways. These pathways then activate second messengers inside the cell, including cAMP or calcium ions.
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...
Many hormones bind to transmembrane G protein-coupled receptors that connect to regulatory G proteins. These G proteins can then activate enzymes such as adenylyl cyclase or phospholipase C. Adenylyl cyclase converts ATP to cAMP, activating...
3.5K
G-protein Coupled Receptors
125.0K
G-protein coupled receptors are ligand binding receptors that indirectly affect changes in the cell. The actual receptor is a single polypeptide that transverses the cell membrane seven times creating intracellular and extracellular loops. The extracellular loops create a ligand specific pocket which binds to neurotransmitters or hormones. The intracellular loops holds onto the G-protein.
125.0K
Cell-surface Signaling
52.7K
Hormones—or any molecule that binds to a receptor, known as a ligand—that are lipid-insoluble (water-soluble) are not able to diffuse across the cell membrane. In order to be able to affect a cell without entering it, these hormones bind to receptors on the cell membrane. When a first messenger, a hormone, binds to a receptor, a signal cascade is set off, causing second messengers, proteins inside the cell, to become activated, resulting in downstream effects.
52.7K
Chemical Signaling in the Endocrine System
4.4K
A signaling cascade is a series of events that facilitates the transmission of information within or between cells, culminating in a targeted response in the recipient cell. As chemical messengers, hormones are pivotal in initiating and modulating these intricate signaling cascades based on their solubility.
Lipid-soluble hormones, such as steroid hormones, demonstrate an intracellular action. These hormones traverse cell membranes due to their lipid nature. Once inside the target cell, they...
Lipid-soluble hormones, such as steroid hormones, demonstrate an intracellular action. These hormones traverse cell membranes due to their lipid nature. Once inside the target cell, they...
4.4K


