Structure basis of CFTR folding, function and pharmacology

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. (C) 2022 Published by Elsevier B.V. on behalf of European Cystic Fibrosis Society.

Automated summary

The loss of function of CFTR protein is the root cause of cystic fibrosis (CF), a common genetic disease. Recent advances in high-throughput drug screening and structural-biology studies have contributed to the development of effective CFTR modulators. This article provides an overview of CFTR folding, function, and pharmacology, with a focus on its first nucleotide-binding domain (NBD1). Understanding the molecular basis of CFTR can inspire the development of mutation-specific CFTR modulators.