Janoš Pavel, Magistrato Alessandra
National Research Council (CNR)-IOM c/o International School for Advanced Studies (SISSA/ISAS), Via Bonomea 265, 34136 Trieste, Italy.
J Chem Inf Model. 2021 Jul 26;61(7):3649-3658. doi: 10.1021/acs.jcim.1c00551. Epub 2021 Jul 2.
The secondary-active Na-K-Cl cotransporter 1 (NKCC1), member of the cation-chloride cotransporter (CCC) family, ensures the electroneutral movement of Cl, Na, and K ions across cellular membranes. NKCC1 regulates Cl homeostasis and cell volume, handling a pivotal role in transepithelial water transport and neuronal excitability. Aberrant NKCC1 transport is hence implicated in a variety of human diseases (hypertension, renal disorders, neuropathies, and cancer). Building on the newly resolved NKCC1 cryo-EM structure, all-atom enhanced sampling simulations unprecedentedly unlock the mechanism of NKCC1-mediated ion transport, assessing the order and the molecular basis of its interdependent ion translocation. Our outcomes strikingly advance the understanding of the physiological mechanism of CCCs and disclose a key role of CCC-conserved asparagine residues, whose side-chain promiscuity ensures the transport of both negatively and positively charged ions along the same translocation route. This study sets a conceptual basis to devise NKCC-selective inhibitors to treat diseases linked to Cl dishomeostasis.
次级主动钠-钾-氯协同转运蛋白1（NKCC1）是阳离子-氯协同转运蛋白（CCC）家族的成员，可确保氯离子、钠离子和钾离子在细胞膜上进行电中性转运。NKCC1调节氯离子稳态和细胞体积，在跨上皮水运输和神经元兴奋性中起关键作用。因此，NKCC1转运异常与多种人类疾病（高血压、肾脏疾病、神经病变和癌症）有关。基于新解析的NKCC1冷冻电镜结构，全原子增强采样模拟前所未有地揭示了NKCC1介导的离子转运机制，评估了其相互依赖的离子转运顺序和分子基础。我们的研究结果显著推进了对CCC生理机制的理解，并揭示了CCC保守天冬酰胺残基的关键作用，其侧链的多用途性确保了带负电和带正电的离子沿着同一条转运途径进行转运。本研究为设计NKCC选择性抑制剂以治疗与氯离子稳态失衡相关的疾病奠定了概念基础。
