Transport and thiazide-inhibition mechanisms of the Na-Cl cotransporter: a structural perspective.

IF 2.2 3区医学 Q3 PERIPHERAL VASCULAR DISEASE

Current Opinion in Nephrology and Hypertension Pub Date : 2025-06-27 DOI:10.1097/MNH.0000000000001099

Chien-Ling Lee, Liang Feng

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Abstract

Purpose of review: The structures of the human sodium-chloride cotransporter (hNCC) and its complex with thiazide diuretics have been determined recently. This review summarizes key structural insights into NCC's transport and inhibition mechanisms.

Recent findings: Recent studies revealed the structures of hNCC and its complex with thiazide diuretics, in inward-facing and outward-facing conformations, respectively. The structures of hNCC in two major conformational states provided important insights into the transport and regulatory mechanisms. Thiazide-bound hNCC structures illuminated the molecular mechanisms of thiazide-mediated NCC inhibition and explained the structure-activity relationship of thiazide diuretics.

Summary: Structures of hNCC provide mechanistic insights into molecular mechanisms of loss-of-function NCC variants that cause Gitelman syndrome. The thiazide-bound hNCC structures provide a blueprint for further optimizing thiazide diuretics to reduce side effects. The novel interdomain interaction-mediated hNCC regulatory mechanisms revealed by structural studies lay the foundation for developing next-generation NCC modulators and NCC-rescuing therapeutics for treating NCC dysfunction.

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Na-Cl共转运体的转运和噻嗪类药物抑制机制：结构视角。

综述目的：最近研究了人氯化钠共转运体（hNCC）及其与噻嗪类利尿剂配合物的结构。这篇综述总结了NCC运输和抑制机制的关键结构见解。最近的发现：最近的研究揭示了hNCC及其与噻嗪类利尿剂配合物的结构，分别为向内和向外的构象。hNCC在两种主要构象状态下的结构为研究转运和调控机制提供了重要的见解。噻嗪类结合的hNCC结构阐明了噻嗪类介导的NCC抑制的分子机制，并解释了噻嗪类利尿剂的构效关系。摘要：hNCC的结构为了解导致Gitelman综合征的功能丧失NCC变异的分子机制提供了机制见解。噻嗪类结合的hNCC结构为进一步优化噻嗪类利尿剂以减少副作用提供了蓝图。结构研究揭示了新的域间相互作用介导的hNCC调控机制，为开发下一代NCC调节剂和治疗NCC功能障碍的NCC挽救疗法奠定了基础。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current Opinion in Nephrology and Hypertension 医学-泌尿学与肾脏学

CiteScore

5.70

自引率

6.20%

发文量

132

审稿时长

6-12 weeks

期刊介绍： A reader-friendly resource, Current Opinion in Nephrology and Hypertension provides an up-to-date account of the most important advances in the field of nephrology and hypertension. Each issue contains either two or three sections delivering a diverse and comprehensive coverage of all the key issues, including pathophysiology of hypertension, circulation and hemodynamics, and clinical nephrology. Current Opinion in Nephrology and Hypertension is an indispensable journal for the busy clinician, researcher or student.