Ligand binding and conformational changes of SUR1 subunit in pancreatic ATP-sensitive potassium channels  

作　　者：Jing-Xiang Wu Dian Ding Mengmeng Wang Yunlu Kang Xin Zeng Lei Chen 

机构地区：[1]State Key Laboratory of Membrane Biology, Institute of Molecular Medicine, Peking University, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Beijing 100871, China [2]Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China [3]Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China

出　　处：《Protein & Cell》2018年第6期553-567,共15页蛋白质与细胞（英文版）

基　　金：The work is supported by grants from the Ministry of Science and Technology of China （National Key R＆D Program of China, 2016YFA0502004 to Lei Chen） and National Natural Science Foundation of China （Grant Nos. 31622021 and 31521062 to Lei Chen） and Young Thousand Talents Program of China to Lei Chen and the China Postdoctoral Science Foundation （2016M600856 and 2017T100014 to Jing-Xiang Wu）. Jing-Xiang Wu is supported by the postdoctoral foundation of the Peking-Tsinghua Center for Life Sci- ences, Peking University.

摘　　要：ATe-sensitive potassium channels （KATP） are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic KATe channels control insulin release and regulate metabo- lism at the whole body level. They are implicated in many metabolic disorders and diseases and are there- fore important drug targets. Here, we present three structures of pancreatic KATe channels solved by cryo- electron microscopy （cryo-EM）, at resolutions ranging from 4.1 to 4.5 A. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 （inward-rectifying potassium channel 6.2） N-ter- minus participates in the coupling between the periph- eral SUR1 （sulfonylurea receptor 1） subunit and the central Kir6.2 channel, reveal the binding mode of acti- vating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains （NBDs） drives a conformational change of the SUR1 subunit.ATe-sensitive potassium channels （KATP） are energy sensors on the plasma membrane. By sensing the intracellular ADP/ATP ratio of β-cells, pancreatic KATe channels control insulin release and regulate metabo- lism at the whole body level. They are implicated in many metabolic disorders and diseases and are there- fore important drug targets. Here, we present three structures of pancreatic KATe channels solved by cryo- electron microscopy （cryo-EM）, at resolutions ranging from 4.1 to 4.5 A. These structures depict the binding site of the antidiabetic drug glibenclamide, indicate how Kir6.2 （inward-rectifying potassium channel 6.2） N-ter- minus participates in the coupling between the periph- eral SUR1 （sulfonylurea receptor 1） subunit and the central Kir6.2 channel, reveal the binding mode of acti- vating nucleotides, and suggest the mechanism of how Mg-ADP binding on nucleotide binding domains （NBDs） drives a conformational change of the SUR1 subunit.

关 键 词：KATP SUR ABC transporter GLIBENCLAMIDE SULFONYLUREA diabetes 

分 类 号：TP312AD[自动化与计算机技术—计算机软件与理论] U455.4[自动化与计算机技术—计算机科学与技术]