PDF(Pubmed)
Abstract：
TRP channels are implicated in various diseases, but high structural similarity between them makes selective pharmacological modulation challenging. Here, we study the molecular mechanism underlying specific inhibition of the TRPM7 channel, which is essential for cancer cell proliferation, by the anticancer agent CCT128930 (CCT). Using cryo-EM, functional analysis, and MD simulations, we show that CCT binds to a vanilloid-like (VL) site, stabilizing TRPM7 in the closed non-conducting state. Similar to other allosteric inhibitors of TRPM7, NS8593 and VER155008, binding of CCT is accompanied by displacement of a lipid that resides in the VL site in the apo condition. Moreover, we demonstrate the principal role of several residues in the VL site enabling CCT to inhibit TRPM7 without impacting the homologous TRPM6 channel. Hence, our results uncover the central role of the VL site for the selective interaction of TRPM7 with small molecules that can be explored in future drug design.
摘要：
TRP通道与各种疾病有关，但是它们之间的高度结构相似性使得选择性药理学调节具有挑战性。这里,我们研究了TRPM7通道特异性抑制的分子机制，这对癌细胞增殖至关重要，由抗癌剂CCT128930（CCT）。使用低温EM，功能分析，和MD模拟，我们显示CCT与香草样样（VL）位点结合，将TRPM7稳定在闭合非导通状态。与TRPM7、NS8593和VER155008的其他变构抑制剂类似,CCT的结合伴随着在apo条件下存在于VL位点的脂质的置换。此外，我们证明了VL位点中几个残基的主要作用,使得CCT能够抑制TRPM7而不影响同源TRPM6通道。因此，我们的结果揭示了VL位点在TRPM7与小分子的选择性相互作用中的核心作用,这可在未来的药物设计中进行探索.
