Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition.
Structures of the TRPM5 channel elucidate mechanisms of activation and inhibition.
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DOI：
10.1038/s41594-021-00607-4
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发表时间：
2021-07
影响因子：
16.8
通讯作者：
Lü W
中科院分区：
文献类型：
--
作者：
Ruan Z;Haley E;Orozco IJ;Sabat M;Myers R;Roth R;Du J;Lü W
Ca 2+激活的TRPM 5通道在味觉感知和胰岛素分泌中起重要作用。然而，Ca 2+调节TRPM 5活性的机制仍然难以捉摸。我们报告冷冻电镜结构的斑马鱼TRPM 5在载脂蛋白封闭状态，钙结合开放状态，拮抗剂结合抑制状态。我们定义了两个新的配体结合位点：胞内结构域（ICD）中的Ca 2+位点（CaICD）和跨膜结构域（TMD）中的拮抗剂位点。CaICD位点是TRPM 5所特有的，并且具有两个作用：调节电压依赖性和促进Ca 2+结合至在整个TRPM通道中保守的CaTMD位点。从两个Ca 2+网站协同启动的构象变化打开离子传导孔。拮抗剂NDNA楔入S1-S4结构域和孔结构域之间的空间，使TMD稳定在apo样闭合状态。本研究结果为深入了解电压依赖性TRPM通道和开发新的治疗药物奠定了基础。
The Ca2+-activated TRPM5 channel plays essential roles in taste perception and insulin secretion. However, the mechanism by which Ca2+ regulates TRPM5 activity remains elusive. We report cryo-EM structures of the zebrafish TRPM5 in an apo closed state, a Ca2+-bound open state, and an antagonist-bound inhibited state. We defined two novel ligand binding sites: a Ca2+ site (CaICD) in the intracellular domain (ICD), and an antagonist site in the transmembrane domain (TMD). The CaICD site is unique to TRPM5 and has two roles: modulating the voltage dependence and promoting Ca2+ binding to the CaTMD site that is conserved throughout TRPM channels. Conformational changes initialized from both Ca2+ sites cooperatively open the ion-conducting pore. The antagonist NDNA wedges into the space between the S1-S4 domain and pore domain, stabilizing the TMD in an apo-like closed state. Our results lay the foundation for understanding the voltage-dependent TRPM channels and developing new therapeutic agents.
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DOI：
10.1107/s2059798318009324
发表时间：
2018-09-01
期刊：
Acta crystallographica. Section D, Structural biology
影响因子：
--
作者：
Afonine PV;Klaholz BP;Moriarty NW;Poon BK;Sobolev OV;Terwilliger TC;Adams PD;Urzhumtsev A
通讯作者：
Urzhumtsev A
DOI：
10.1007/s00424-010-0835-z
发表时间：
2010-06
期刊：
Pflugers Archiv : European journal of physiology
影响因子：
--
作者：
Brixel LR;Monteilh-Zoller MK;Ingenbrandt CS;Fleig A;Penner R;Enklaar T;Zabel BU;Prawitt D
通讯作者：
Prawitt D
影响因子：
16.2
作者：
Liu C;Reese R;Vu S;Rougé L;Shields SD;Kakiuchi-Kiyota S;Chen H;Johnson K;Shi YP;Chernov-Rogan T;Greiner DMZ;Kohli PB;Hackos D;Brillantes B;Tam C;Li T;Wang J;Safina B;Magnuson S;Volgraf M;Payandeh J;Zheng J;Rohou A;Chen J
通讯作者：
Chen J
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
Emsley, P;Cowtan, K
通讯作者：
Cowtan, K
影响因子：
7.7
作者：
Bai, Xiao-chen;Rajendra, Eeson;Scheres, Sjors H. W.
通讯作者：
Scheres, Sjors H. W.