9C0G

Phosphorylated human NKCC1 in complex with torsemide

これはPDB形式変換不可エントリーです。

9C0G の概要

• エントリーDOI: 10.2210/pdb9c0g/pdb
• EMDBエントリー: 45083
• 分子名称: Solute carrier family 12 member 2, 4-(3-methylanilino)-N-[(propan-2-yl)carbamoyl]pyridine-3-sulfonamide, CHLORIDE ION, ... (5 entities in total)
• 機能のキーワード: phosphorylation, sodium potassium chloride cotransporter, outward-open, torsemide, transport protein
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 264140.54

構造登録者

Zhao, Y.X.,Cao, E.H. (登録日: 2024-05-25, 公開日: 2025-02-12, 最終更新日: 2025-03-19)

主引用文献

Zhao, Y.,Vidossich, P.,Forbush, B.,Ma, J.,Rinehart, J.,De Vivo, M.,Cao, E.
Structural basis for human NKCC1 inhibition by loop diuretic drugs.
Embo J., 44:1540-1562, 2025

PubMed Abstract: Na-K-Cl cotransporters functions as an anion importers, regulating trans-epithelial chloride secretion, cell volume, and renal salt reabsorption. Loop diuretics, including furosemide, bumetanide, and torsemide, antagonize both NKCC1 and NKCC2, and are first-line medicines for the treatment of edema and hypertension. NKCC1 activation by the molecular crowding sensing WNK kinases is critical if cells are to combat shrinkage during hypertonic stress; however, how phosphorylation accelerates NKCC1 ion transport remains unclear. Here, we present co-structures of phospho-activated NKCC1 bound with furosemide, bumetanide, or torsemide showing that furosemide and bumetanide utilize a carboxyl group to coordinate and co-occlude a K, whereas torsemide encroaches and expels the K from the site. We also found that an amino-terminal segment of NKCC1, once phosphorylated, interacts with the carboxyl-terminal domain, and together, they engage with intracellular ion exit and appear to be poised to facilitate rapid ion translocation. Together, these findings enhance our understanding of NKCC-mediated epithelial ion transport and the molecular mechanisms of its inhibition by loop diuretics.

PubMed: 39875725
DOI: 10.1038/s44318-025-00368-6

実験手法

ELECTRON MICROSCOPY (2.6 Å)