Lee Chien-Ling, Feng Liang
Department of Molecular and Cellular Physiology, Stanford University School of Medicine, Stanford, California, USA.
Curr Opin Nephrol Hypertens. 2025 Sep 1;34(5):440-449. doi: 10.1097/MNH.0000000000001099. Epub 2025 Jul 3.
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 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.
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.
人类氯化钠共转运体（hNCC）的结构及其与噻嗪类利尿剂的复合物结构最近已被确定。本综述总结了关于NCC转运和抑制机制的关键结构见解。
最近的研究分别揭示了hNCC及其与噻嗪类利尿剂复合物处于向内构象和向外构象时的结构。hNCC在两种主要构象状态下的结构为转运和调节机制提供了重要见解。与噻嗪类结合的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。
hNCC的结构为导致吉特曼综合征的功能丧失型NCC变体的分子机制提供了机制性见解。与噻嗪类结合的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。结构研究揭示的新型结构域间相互作用介导的hNCC调节机制为开发下一代NCC调节剂和治疗NCC功能障碍的NCC挽救疗法奠定了基础。
