Department of Biochemistry and Molecular Biophysics, Columbia University, New York, NY, USA.
Walther-Straub Institute of Pharmacology and Toxicology, LMU Munich, Munich, Germany.
Nat Commun. 2023 May 8;14(1):2639. doi: 10.1038/s41467-023-38362-3.
The transient receptor potential channel TRPM7 is a master regulator of the organismal balance of divalent cations that plays an essential role in embryonic development, immune responses, cell mobility, proliferation, and differentiation. TRPM7 is implicated in neuronal and cardiovascular disorders, tumor progression and has emerged as a new drug target. Here we use cryo-EM, functional analysis, and molecular dynamics simulations to uncover two distinct structural mechanisms of TRPM7 activation by a gain-of-function mutation and by the agonist naltriben, which show different conformational dynamics and domain involvement. We identify a binding site for highly potent and selective inhibitors and show that they act by stabilizing the TRPM7 closed state. The discovered structural mechanisms provide foundations for understanding the molecular basis of TRPM7 channelopathies and drug development.
瞬时受体电位通道 TRPM7 是二价阳离子体平衡的主要调节剂，在胚胎发育、免疫反应、细胞迁移、增殖和分化中发挥着重要作用。TRPM7 与神经元和心血管疾病、肿瘤进展有关，并已成为新的药物靶点。在这里，我们使用冷冻电镜、功能分析和分子动力学模拟来揭示 gain-of-function 突变和激动剂 naltriben 激活 TRPM7 的两种不同结构机制，它们显示出不同的构象动力学和结构域参与。我们确定了一个高活性和选择性抑制剂的结合位点，并表明它们通过稳定 TRPM7 的关闭状态发挥作用。所发现的结构机制为理解 TRPM7 通道病和药物开发的分子基础提供了基础。
