Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.
Structure and thiazide inhibition mechanism of the human Na-Cl cotransporter.
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DOI：
10.1038/s41586-023-05718-0
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发表时间：
2023-02
期刊：
影响因子：
64.8
通讯作者：
Feng, Liang
中科院分区：
文献类型：
--
作者：
Fan, Minrui;Zhang, Jianxiu;Lee, Chien-Ling;Zhang, Jinru;Feng, Liang
钠-氯协同转运蛋白（NCC）对肾脏生理至关重要。NCC在肾单位的远曲小管中的盐重吸收中起主要作用，并且NCC的突变引起盐消耗性疾病Gitelman综合征。作为盐处理的关键参与者，NCC调节血压，是噻嗪类利尿剂的目标，噻嗪类利尿剂已被广泛用作治疗高血压的一线药物60多年。在这里，我们确定了冷冻电镜（cryo-EM）结构的人NCC单独和复杂的常用噻嗪类利尿剂。这些结构，连同功能的研究，揭示了主要的构象状态的NCC和一个有趣的调节机制。他们还阐明了噻嗪类利尿剂如何与NCC特异性相互作用并抑制其转运功能。我们的研究结果为理解NCC的Na-Cl共转运机制提供了重要的见解，并为未来的药物设计和解释疾病相关突变建立了框架。
The sodium-chloride cotransporter (NCC) is critical for kidney physiology. NCC plays a major role in salt reabsorption in the distal convoluted tubule of the nephron, and mutations in NCC cause the salt-wasting disease Gitelman syndrome. As a key player in salt handling, NCC regulates blood pressure and is the target of thiazide diuretics, which have been widely prescribed as first-line medications to treat hypertension for more than 60 years. Here we determined the cryo-electron microscopy (cryo-EM) structures of human NCC alone and in complex with a commonly used thiazide diuretic. These structures, together with functional studies, reveal major conformational states of NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with NCC and inhibit its transport function. Our results provide critical insights for understanding the Na-Cl cotransport mechanism of NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.
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影响因子：
64.8
作者：
Jumper J;Evans R;Pritzel A;Green T;Figurnov M;Ronneberger O;Tunyasuvunakool K;Bates R;Žídek A;Potapenko A;Bridgland A;Meyer C;Kohl SAA;Ballard AJ;Cowie A;Romera-Paredes B;Nikolov S;Jain R;Adler J;Back T;Petersen S;Reiman D;Clancy E;Zielinski M;Steinegger M;Pacholska M;Berghammer T;Bodenstein S;Silver D;Vinyals O;Senior AW;Kavukcuoglu K;Kohli P;Hassabis D
通讯作者：
Hassabis D
影响因子：
30.8
作者：
Lalioti, Maria D.;Zhang, Junhui;Lifton, Richard P.
通讯作者：
Lifton, Richard P.
DOI：
10.1001/jama.1958.02990020025004
发表时间：
1958-01-01
影响因子：
120.7
作者：
FREIS, ED;WANKO, A;PARRISH, AE
通讯作者：
PARRISH, AE
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
DOI：
10.1107/s0907444909052925
发表时间：
2010-02
期刊：
Acta crystallographica. Section D, Biological crystallography
影响因子：
--
作者：
Adams PD;Afonine PV;Bunkóczi G;Chen VB;Davis IW;Echols N;Headd JJ;Hung LW;Kapral GJ;Grosse-Kunstleve RW;McCoy AJ;Moriarty NW;Oeffner R;Read RJ;Richardson DC;Richardson JS;Terwilliger TC;Zwart PH
通讯作者：
Zwart PH