Cryo-EM reveals ligand induced allostery underlying InsP3R channel gating  

作　　者：Guizhen Fan Mariah R. Baker Zhao Wang Alexander B. Seryshev Steven J. Ludtke Matthew L. Baker Irina I. Serysheva 

机构地区：[1]Department of Biochemistry and Molecular Biology,Structural Biology Imaging Center,McGovern Medical School at The University of Texas Health Science Center at Houston, 6431 Fannin Street,Houston,TX 77030,USA [2]Verna and Marts McLean Department of Biochemistry and Molecular Biology,CryoEM and CryoET Core,Baylor College of Medicine,One Baylor Plaza,Houston,TX 77030,USA

出　　处：《Cell Research》2018年第12期1158-1170,共13页细胞研究（英文版）

基　　金：the National Institutes of Health (ROIGM072804,R21AR063255,R21NS106968, ROIGM080139,P41GM103832,American Heart Association (16GRNT2972000);Muscular Dystrophy Association (295138);National Science Foundation (DBI-1356306).

摘　　要：Inositol-1,4,5-trisphosphate receptors (InsP3Rs) are cation channels that mobilize Ca2+ from intracellular stores in response to a wide range of cellular stimuli.The paradigm of InsP3R activation is the coupled interplay between binding of InsP3 and Ca2+ that switches the ion conduction pathway between closed and open states to enable the passage of Ca^2+ through the channel.However,the molecular mechanism of how the receptor senses and decodes ligand-binding signals into gating motion remains unknown.Here,we present the electron cryo-microscopy structure of InsP3R1 from rat cerebellum determined to 4.1 A resolution in the presence of activating concentrations of Ca2+ and adenophostin A (AdA),a structural mimetic of InsP3 and the most potent known agonist of the channel.Comparison with the 3.9 A-resolution structure of InsP3R1 in the Apo-state,also reported herein,reveals the binding arrangement of AdA in the tetrameric channel assembly and striking ligand-Induced conformational rearrangements within cytoplasmic domains coupled to the dilation of a hydrophobic constriction at the gate.Together,our results provide critical insights into the mechanistic principles by which ligand-binding allosterically gates InsP3R channel.

关 键 词：CRYO-EM REVEALS LIGAND ALLOSTERY UNDERLYING InsP3R channel GATING 

分 类 号：Q[生物学]