Structural basis for CFTR inhibition by CFTRinh-172.

TitleStructural basis for CFTR inhibition by CFTRinh-172.
Publication TypeJournal Article
Year of Publication2024
AuthorsYoung PG, Levring J, Fiedorczuk K, Blanchard SC, Chen J
JournalProc Natl Acad Sci U S A
Volume121
Issue10
Paginatione2316675121
Date Published2024 Mar 05
ISSN1091-6490
KeywordsAdenosine Triphosphate, Benzoates, Cystic Fibrosis Transmembrane Conductance Regulator, Dimerization, 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.

DOI10.1073/pnas.2316675121
Alternate JournalProc Natl Acad Sci U S A
PubMed ID38422021
PubMed Central IDPMC10927578
Grant ListR01 GM079238 / GM / NIGMS NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States
GM079238 / GF / NIH HHS / United States
T32GM007739 / GF / NIH HHS / United States

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