Laboratory of Biophysics of Synaptic Processes, Sechenov Institute of Evolutionary Physiology and Biochemistry, Russian Academy of Sciences, St. Petersburg 194223, Russia.
Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
Int J Mol Sci. 2021 Jul 29;22(15):8143. doi: 10.3390/ijms22158143.
The superfamily of P-loop channels includes various potassium channels, voltage-gated sodium and calcium channels, transient receptor potential channels, and ionotropic glutamate receptors. Despite huge structural and functional diversity of the channels, their pore-forming domain has a conserved folding. In the past two decades, scores of atomic-scale structures of P-loop channels with medically important drugs in the inner pore have been published. High structural diversity of these complexes complicates the comparative analysis of these structures. Here we 3D-aligned structures of drug-bound P-loop channels, compared their geometric characteristics, and analyzed the energetics of ligand-channel interactions. In the superimposed structures drugs occupy most of the sterically available space in the inner pore and subunit/repeat interfaces. Cationic groups of some drugs occupy vacant binding sites of permeant ions in the inner pore and selectivity-filter region. Various electroneutral drugs, lipids, and detergent molecules are seen in the interfaces between subunits/repeats. In many structures the drugs strongly interact with lipid and detergent molecules, but physiological relevance of such interactions is unclear. Some eukaryotic sodium and calcium channels have state-dependent or drug-induced π-bulges in the inner helices, which would be difficult to predict. The drug-induced π-bulges may represent a novel mechanism of gating modulation.
P 环通道超家族包括各种钾通道、电压门控钠和钙通道、瞬时受体电位通道和离子型谷氨酸受体。尽管通道在结构和功能上存在巨大差异，但它们的孔形成域具有保守的折叠。在过去的二十年中，已经发表了大量具有医学重要性的药物在内腔的 P 环通道的原子尺度结构。这些复合物的高结构多样性使得对这些结构的比较分析变得复杂。在这里，我们对结合药物的 P 环通道进行了 3D 对齐结构，比较了它们的几何特征，并分析了配体-通道相互作用的能量。在叠加结构中，药物占据了内腔和亚基/重复界面中大部分可用的空间。一些药物的阳离子基团占据了内腔和选择性滤过区中可渗透离子的空位结合位点。各种电中性药物、脂质和去污剂分子出现在亚基/重复之间的界面上。在许多结构中，药物与脂质和去污剂分子强烈相互作用，但这种相互作用的生理相关性尚不清楚。一些真核钠和钙通道在内螺旋中具有与状态相关或药物诱导的 π 凸起，这将很难预测。药物诱导的 π 凸起可能代表一种新的门控调节机制。
