小柯机器人

研究揭示人类Na-Cl共转运体的结构及噻嗪抑制机制
2023-02-16 16:40

美国斯坦福大学Liang Feng研究团队报道人类Na-Cl共转运体的结构及噻嗪抑制机制。相关论文于2023年2月15日在线发表在《自然》杂志上。

研究人员利用冷冻电镜确定了人类钠-氯化钠共转运体(NCC)单独以及与常见使用的噻嗪类利尿剂复合的结构。这些结构以及功能研究揭示了NCC的主要构象状态和有趣的调控机制。研究人员还阐明了噻嗪类利尿剂是如何具体地与NCC相互作用并抑制其运输功能的。这些结果为理解NCC的Na-Cl共转运机制提供了关键的见解,并为未来的药物设计和解释疾病相关突变建立了一个框架。

据悉,NCC对肾脏生理至关重要。NCC在肾元远曲小管的盐重吸收中起主要作用,NCC的突变与盐消耗病Gitelman综合征有关。作为盐处理中的关键角色,NCC调节血压,是噻嗪类利尿剂的靶标,噻嗪类利尿剂已被广泛用作治疗高血压的一线药物超过60年。

附:英文原文

Title: Structure and thiazide inhibition mechanism of the human Na–Cl cotransporter

Author: Fan, Minrui, Zhang, Jianxiu, Lee, Chien-Ling, Zhang, Jinru, Feng, Liang

Issue&Volume: 2023-02-15

Abstract: The sodium–chloride cotransporter (NCC) is critical for kidney physiology1. The NCC has a major role in salt reabsorption in the distal convoluted tubule of the nephron2,3, and mutations in the NCC cause the salt-wasting disease Gitelman syndrome4. As a key player in salt handling, the 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 years5,6,7. Here we determined the structures of human NCC alone and in complex with a commonly used thiazide diuretic using cryo-electron microscopy. These structures, together with functional studies, reveal major conformational states of the NCC and an intriguing regulatory mechanism. They also illuminate how thiazide diuretics specifically interact with the NCC and inhibit its transport function. Our results provide critical insights for understanding the Na–Cl cotransport mechanism of the NCC, and they establish a framework for future drug design and for interpreting disease-related mutations.

DOI: 10.1038/s41586-023-05718-0

Source: https://www.nature.com/articles/s41586-023-05718-0

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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