Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland.
Institute of Molecular Biology and Biophysics, ETH Zurich, Zurich, Switzerland.
Nat Commun. 2022 Nov 7;13(1):6714. doi: 10.1038/s41467-022-34284-8.
Organic cation transporters (OCTs) facilitate the translocation of catecholamines, drugs and xenobiotics across the plasma membrane in various tissues throughout the human body. OCT3 plays a key role in low-affinity, high-capacity uptake of monoamines in most tissues including heart, brain and liver. Its deregulation plays a role in diseases. Despite its importance, the structural basis of OCT3 function and its inhibition has remained enigmatic. Here we describe the cryo-EM structure of human OCT3 at 3.2 Å resolution. Structures of OCT3 bound to two inhibitors, corticosterone and decynium-22, define the ligand binding pocket and reveal common features of major facilitator transporter inhibitors. In addition, we relate the functional characteristics of an extensive collection of previously uncharacterized human genetic variants to structural features, thereby providing a basis for understanding the impact of OCT3 polymorphisms.
有机阳离子转运体（OCTs）促进儿茶酚胺、药物和外源性化学物质在人体各种组织的质膜中转运。OCT3 在大多数组织（包括心脏、大脑和肝脏）中发挥着关键作用，能够低亲和力、高容量摄取单胺类物质。其失调与疾病的发生有关。尽管其具有重要性，但 OCT3 的功能和抑制作用的结构基础仍然是个谜。在这里，我们描述了人源 OCT3 的冷冻电镜结构，分辨率为 3.2 Å。与两种抑制剂（皮质酮和地西他滨）结合的 OCT3 结构定义了配体结合口袋，并揭示了主要促进剂转运蛋白抑制剂的共同特征。此外，我们将大量以前未表征的人类遗传变异的功能特征与结构特征联系起来，从而为理解 OCT3 多态性的影响提供了基础。
