当前位置:科学网首页 > 小柯机器人 >详情
TRPM8蛋白结构被解析
作者:小柯机器人 发布时间:2019/9/6 13:31:05

美国加州大学旧金山分校David Julius和Yifan Cheng等研究人员合作解析了TRPM8蛋白的结构,为其抑制与脱敏提供了新的见解。相关论文2019年9月5日在线发表在《科学》上。

研究人员报道了TRPM8的无配体、拮抗剂结合形式或钙结合形式的冷冻电镜结构,揭示了强烈的构象变化如何产生两种非导电状态,闭合和脱敏。研究人员描述了一种可延展的配体结合口袋,其容纳具有不同化学结构的药物,并描绘了离子渗透途径,包括脂质对孔结构的贡献。此外,研究人员发现直接钙结合介导刺激引起的脱敏,从而揭示了这种感受适应的重要机制。研究人员观察到S4-S5衔接处内大量重排,其相对于TRP螺旋重新定位了S1-S4和孔结构域,这让研究人员提出了用于调节TRPM8以及可能的其他TRP通道的独特模型。

据悉,TRPM8蛋白是环境寒冷的主要检测者,也是治疗病理性冷超敏的重要靶点。

附:英文原文

Title: Structural insights into TRPM8 inhibition and desensitization

Author: Melinda M. Diver, Yifan Cheng, David Julius

Issue&Volume: 2019/09/05

Abstract: TRPM8 is the primary detector of environmental cold and an important target for treating pathological cold hypersensitivity. Here, we present cryo-EM structures of TRPM8 in ligand-free, antagonist- or calcium-bound forms, revealing how robust conformational changes give rise to two non-conducting states, closed and desensitized. We describe a malleable ligand-binding pocket that accommodates drugs of diverse chemical structures, and delineate the ion permeation pathway, including the contribution of lipids to pore architecture. Furthermore, we show that direct calcium binding mediates stimulus-evoked desensitization, clarifying this important mechanism of sensory adaptation. We observe large rearrangements within the S4-S5 linker that reposition the S1-S4 and pore domains relative to the TRP helix, leading us to propose a distinct model for modulation of TRPM8 and possibly other TRP channels.

DOI: 10.1126/science.aax6672

Source:https://science.sciencemag.org/content/early/2019/09/04/science.aax6672

期刊信息
Science:《科学》,创刊于1880年。隶属于美国科学促进会,最新IF:41.037