Structural basis for CFTR inhibition by CFTRinh-172.

Publication Type	Academic Article
Authors	Young P, Levring J, Fiedorczuk K, Blanchard S, Chen J
Journal	Proc Natl Acad Sci U S A
Volume	121
Issue	10
Pagination	e2316675121
Date Published	02/29/2024
ISSN	1091-6490
Keywords	Cystic Fibrosis Transmembrane Conductance Regulator, Adenosine Triphosphate, Thiazolidines
Abstract	The cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that regulates electrolyte and fluid balance in epithelial tissues. While activation of CFTR is vital to treating cystic fibrosis, selective inhibition of CFTR is a potential therapeutic strategy for secretory diarrhea and autosomal dominant polycystic kidney disease. Although several CFTR inhibitors have been developed by high-throughput screening, their modes of action remain elusive. In this study, we determined the structure of CFTR in complex with the inhibitor CFTRinh-172 to an overall resolution of 2.7 Å by cryogenic electron microscopy. We observe that CFTRinh-172 binds inside the pore near transmembrane helix 8, a critical structural element that links adenosine triphosphate hydrolysis with channel gating. Binding of CFTRinh-172 stabilizes a conformation in which the chloride selectivity filter is collapsed, and the pore is blocked from the extracellular side of the membrane. Single-molecule fluorescence resonance energy transfer experiments indicate that CFTRinh-172 inhibits channel gating without compromising nucleotide-binding domain dimerization. Together, these data reconcile previous biophysical observations and provide a molecular basis for the activity of this widely used CFTR inhibitor.
DOI	10.1073/pnas.2316675121
PubMed ID	38422021
PubMed Central ID	PMC10927578