小柯机器人

美国洛克菲勒大学Jue Chen等研究人员合作揭示单分子分辨率下的CFTR功能、病理学和药理学。2023年3月22日，《自然》杂志在线发表了这一最新研究成果。

研究人员结合集合功能测量、单分子荧光共振能量转移、电生理学和动力学模拟，表明人类囊性纤维化跨膜传导调节器（CFTR）的两个核苷酸结合结构域（NBD）在通道开放前发生二聚反应。CFTR表现出一种异构门控机制，其中NBD二聚体通道内的构象变化受ATP水解的支配，调节氯化物的传导。增效剂ivacaftor和GLPG1837通过在NBD二聚化时增加孔的开放来增强通道活性。在ATP酶位点的近端（G551D）或远端（L927P）的致病替代都会降低NBD二聚化的效率。这些发现共同促成了一个门控机制的框架，为寻找更有效的临床治疗方法提供了参考。

据介绍，CFTR是一个阴离子通道，调节上皮细胞膜上的盐和液体平衡。CFTR的改变导致囊性纤维化，这是一种无法治愈的致命疾病。几十年来，人们一直在分析CFTR的电生理特性。CFTR的结构被确定为两个全局性不同的构象，强调了它与其他ATP结合盒式转运体的演化关系。然而，目前还缺乏CFTR的基本功能与现存结构之间的直接联系。

附：英文原文

Title: CFTR function, pathology and pharmacology at single-molecule resolution

Author: Levring, Jesper, Terry, Daniel S., Kilic, Zeliha, Fitzgerald, Gabriel, Blanchard, Scott, Chen, Jue

Issue&Volume: 2023-03-22

Abstract: The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates salt and fluid homeostasis across epithelial membranes1. Alterations in CFTR cause cystic fibrosis, a fatal disease without a cure2,3. Electrophysiological properties of CFTR have been analysed for decades4,5,6. The structure of CFTR, determined in two globally distinct conformations, underscores its evolutionary relationship with other ATP-binding cassette transporters. However, direct correlations between the essential functions of CFTR and extant structures are lacking at present. Here we combine ensemble functional measurements, single-molecule fluorescence resonance energy transfer, electrophysiology and kinetic simulations to show that the two nucleotide-binding domains (NBDs) of human CFTR dimerize before channel opening. CFTR exhibits an allosteric gating mechanism in which conformational changes within the NBD-dimerized channel, governed by ATP hydrolysis, regulate chloride conductance. The potentiators ivacaftor and GLPG1837 enhance channel activity by increasing pore opening while NBDs are dimerized. Disease-causing substitutions proximal (G551D) or distal (L927P) to the ATPase site both reduce the efficiency of NBD dimerization. These findings collectively enable the framing of a gating mechanism that informs on the search for more efficacious clinical therapies.

DOI: 10.1038/s41586-023-05854-7

Source: https://www.nature.com/articles/s41586-023-05854-7

Nature：《自然》，创刊于1869年。隶属于施普林格·自然出版集团，最新IF：69.504
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