Department of Structural Biochemistry, Max Planck Institute of Molecular Physiology, Dortmund, Germany.
Department of Neurophysiology, Physiological Institute, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
Elife. 2020 Nov 25;9:e60603. doi: 10.7554/eLife.60603.
Canonical transient receptor potential channels (TRPC) are involved in receptor-operated and/or store-operated Ca signaling. Inhibition of TRPCs by small molecules was shown to be promising in treating renal diseases. In cells, the channels are regulated by calmodulin (CaM). Molecular details of both CaM and drug binding have remained elusive so far. Here, we report structures of TRPC4 in complex with three pyridazinone-based inhibitors and CaM. The structures reveal that all the inhibitors bind to the same cavity of the voltage-sensing-like domain and allow us to describe how structural changes from the ligand-binding site can be transmitted to the central ion-conducting pore of TRPC4. CaM binds to the rib helix of TRPC4, which results in the ordering of a previously disordered region, fixing the channel in its closed conformation. This represents a novel CaM-induced regulatory mechanism of canonical TRP channels.
经典瞬时受体电位通道（TRPC）参与受体操纵和/或储存操纵的 Ca 信号传导。小分子抑制 TRPC 被证明在治疗肾脏疾病方面有很大的前景。在细胞中，通道受钙调蛋白（CaM）调节。到目前为止，CaM 和药物结合的分子细节仍然难以捉摸。在这里，我们报告了 TRPC4 与三种哒嗪酮基抑制剂和 CaM 复合物的结构。这些结构揭示了所有抑制剂都结合到电压感应样结构域的相同腔中，使我们能够描述配体结合位点的结构变化如何传递到 TRPC4 的中央离子传导孔。CaM 结合到 TRPC4 的核糖体螺旋，导致之前无序区域的有序化，使通道固定在其关闭构象。这代表了经典 TRP 通道的一种新型 CaM 诱导调节机制。
