Institute of Pharmacology, School of Medicine, National Yang Ming Chiao Tung University, Taiwan; Department of Medical Pharmacology and Physiology, Dalton Cardiovascular Research Center, University of Missouri, Columbia, MO, USA.
Cellular Protein Chemistry, Bijvoet Centre for Biomolecular Research, Utrecht University, 3584 CH Utrecht, The Netherlands.
J Cyst Fibros. 2023 Mar;22 Suppl 1:S5-S11. doi: 10.1016/j.jcf.2022.09.010. Epub 2022 Oct 8.
The root cause of cystic fibrosis (CF), the most common life-shortening genetic disease in the Caucasian population, is the loss of function of the CFTR protein, which serves as a phosphorylation-activated, ATP-gated anion channel in numerous epithelia-lining tissues. In the past decade, high-throughput drug screening has made a significant stride in developing highly effective CFTR modulators for the treatment of CF. Meanwhile, structural-biology studies have succeeded in solving the high-resolution three-dimensional (3D) structure of CFTR in different conformations. Here, we provide a brief overview of some striking features of CFTR folding, function and pharmacology, in light of its specific structural features within the ABC-transporter superfamily. A particular focus is given to CFTR's first nucleotide-binding domain (NBD1), because folding of NBD1 constitutes a bottleneck in the CFTR protein biogenesis pathway, and ATP binding to this domain plays a unique role in the functional stability of CFTR. Unraveling the molecular basis of CFTR folding, function, and pharmacology would inspire the development of next-generation mutation-specific CFTR modulators.
囊性纤维化（CF）是白种人群中最常见的缩短寿命的遗传疾病，其根本原因是 CFTR 蛋白的功能丧失，CFTR 蛋白作为一种磷酸化激活、ATP 门控的阴离子通道存在于众多上皮衬里组织中。在过去的十年中，高通量药物筛选在开发用于治疗 CF 的高效 CFTR 调节剂方面取得了重大进展。同时，结构生物学研究成功解决了 CFTR 在不同构象下的高分辨率三维（3D）结构。在这里，我们根据 CFTR 在 ABC 转运蛋白超家族中的特定结构特征，简要概述了 CFTR 折叠、功能和药理学的一些显著特征。特别关注 CFTR 的第一个核苷酸结合域（NBD1），因为 NBD1 的折叠构成 CFTR 蛋白生物发生途径中的一个瓶颈，并且该结构域与 ATP 的结合在 CFTR 的功能稳定性中起着独特的作用。阐明 CFTR 折叠、功能和药理学的分子基础将激发下一代针对突变的 CFTR 调节剂的开发。
