ArticleNature communications2024
Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.
Article in Nature communications, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed.
- BEST4⁺ cells: a potential hub of intestinal ion transport and diarrhea manipulation.Advanced biotechnology · 2026Review
- Epithelial plasma membrane transporters as drug targets.Physiological reviews · 2026Review
- Reconstitution of CFTR ubiquitination identifies lysine-420 as a regulator of cell surface residence and current.Biochemistry and biophysics reports · 2026Article
- Effects of cAMP and CFTR modulation on apical fluid pH in human airway Calu-3 cells.Physiological reports · 2026Article
- Huangjin Shuangshen decoction alleviates chronic atrophic gastritis by suppressing TNF/NF-κB signaling and promoting CFTR-associated gastric mucosal barrier repair.Frontiers in immunology · 2026Article
- Seminal fluid extracellular vesicles restore human sperm osmoregulation after cystic fibrosis transmembrane conductance regulator inhibition.Scientific reports · 2025Article
- Targeting the Aryl Hydrocarbon Receptor: The Potential of Indole Compounds in the Treatment of Cystic Fibrosis.International journal of molecular sciences · 2025Review
- Molecular and pharmacological evaluation of rare, cystic fibrosis-causing missense mutations of the CFTR channel.The Journal of physiology · 2025Article
- Structure of CFTR bound to (R)-BPO-27 unveils a pore-blockage mechanism.Nature communications · 2025Article
- Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators.iScience · 2025Article
- VX-770, CInternational journal of molecular sciences · 2025Article
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
Corrections and comments
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Authors and funding
9 authors.
Funding
Abstract
Loss-of-function mutations of the CFTR gene cause the life-shortening genetic disease cystic fibrosis (CF), whereas overactivity of CFTR may lead to secretory diarrhea and polycystic kidney disease. While effective drugs targeting the CFTR protein have been developed for the treatment of CF, little progress has been made for diseases caused by hyper-activated CFTR. Here, we solve the cryo-EM structure of CFTR in complex with CFTRinh-172 (Inh-172), a CFTR gating inhibitor with promising potency and efficacy. We find that Inh-172 binds inside the pore of CFTR, interacting with amino acid residues from transmembrane segments (TMs) 1, 6, 8, 9, and 12 through mostly hydrophobic interactions and a salt bridge. Substitution of these residues lowers the apparent affinity of Inh-172. The inhibitor-bound structure reveals re-orientations of the extracellular segment of TMs 1, 8, and 12, supporting an allosteric modulation mechanism involving post-binding conformational changes. This allosteric inhibitory mechanism readily explains our observations that pig CFTR, which preserves all the amino acid residues involved in Inh-172 binding, exhibits a much-reduced sensitivity to Inh-172 and that the apparent affinity of Inh-172 is altered by the CF drug ivacaftor (i.e., VX-770) which enhances CFTR's activity through binding to a site also comprising TM8.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.