The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel
The Structural Basis for the Binding of Repaglinide to the Pancreatic KATP Channel
复制标题
DOI：
10.1016/j.celrep.2019.04.050
复制
发表时间：
2019-05-07
期刊：
影响因子：
8.8
通讯作者：
Chen, Lei
中科院分区：
文献类型：
--
作者：
Ding, Dian;Wang, Mengmeng;Chen, Lei
瑞格列奈 (RPG) 是一种短效胰岛素促分泌剂，广泛用于治疗 2 型糖尿病。它通过抑制胰腺 ATP 敏感钾通道 (K-ATP) 来促进胰岛素分泌。然而，人们对 RPG 与 K-ATP 通道结合的机制知之甚少。在这里，我们描述了两种冷冻电镜结构：与抑制性 RPG 和 3.3 埃的腺苷-5'-(γ-硫代)-三磷酸 (ATP gamma S) 复合的胰腺 K-ATP 通道，以及 RPG 结合的迷你 SUR1 蛋白的中等分辨率结构，其中内向整流钾通道 6.1 (Kir6.1) 的 N 末端与磺酰脲类的 ABC 转运蛋白模块融合受体 1 (SUR1)。这些结构揭示了 SUR1 亚基中 RPG 的结合位点。此外，高分辨率结构揭示了 ATP 结合位点的复杂结构，该结合位点由 Kir6.2 和 SUR1 亚基以及域-域相互作用界面形成。
Repaglinide (RPG) is a short-acting insulin secretagogue widely prescribed for the treatment of type 2 diabetes. It boosts insulin secretion by inhibiting the pancreatic ATP-sensitive potassium channel (K-ATP). However, the mechanisms by which RPG binds to the K-ATP channel are poorly understood. Here, we describe two cryo-EM structures: the pancreatic K-ATP channel in complex with inhibitory RPG and adenosine-5'-(gamma-thio)-triphosphate (ATP gamma S) at 3.3 angstrom and a medium-resolution structure of a RPG-bound mini SUR1 protein in which the N terminus of the inward-rectifying potassium channel 6.1 (Kir6.1) is fused to the ABC transporter module of the sulfonylurea receptor 1 (SUR1). These structures reveal the binding site of RPG in the SUR1 subunit. Furthermore, the high-resolution structure reveals the complex architecture of the ATP binding site, which is formed by both Kir6.2 and SUR1 subunits, and the domain-domain interaction interfaces.