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

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.