ArticleeLife2021
Molecular pathology of the R117H cystic fibrosis mutation is explained by loss of a hydrogen bond.
Article in eLife, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 13 papers, 1 of them a synthesis that pooled it.
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Who cites it
13 citing papers in PubMed, 1 synthesis or guideline pooled it, 20 citations in OpenAlex.
- Bicarbonate defective CFTR variants increase risk for chronic pancreatitis: A meta-analysis.PloS one · 2022Pooled it
- Regulation and function of specialized membrane protrusions in intercellular communication.Nature reviews. Molecular cell biology · 2026Review
- Genetically engineered approaches to the treatment of cystic fibrosis.Biophysical reviews · 2025Review
- Structural determinants of protein kinase A essential for CFTR channel activation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- The structures of protein kinase A in complex with CFTR: Mechanisms of phosphorylation and noncatalytic activation.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Investigation of CFTR Function in Human Nasal Epithelial Cells Informs Personalized Medicine.American journal of respiratory cell and molecular biology · 2024Article
- Allosteric inhibition of CFTR gating by CFTRinh-172 binding in the pore.Nature communications · 2024Article
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- Estimating the true stability of the prehydrolytic outward-facing state in an ABC protein.eLife · 2023Article
- Tweaking the catalytic efficiency of the CFTR ion channel.The Journal of general physiology · 2023Article
- Optimization of CFTR gating through the evolution of its extracellular loops.The Journal of general physiology · 2023Article
- Impact ofInternational journal of molecular sciences · 2022Review
- Molecular mechanisms of cystic fibrosis - how mutations lead to misfunction and guide therapy.Bioscience reports · 2022Review
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The phosphorylation-activated anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is gated by an ATP hydrolysis cycle at its two cytosolic nucleotide-binding domains, and is essential for epithelial salt-water transport. A large number of CFTR mutations cause cystic fibrosis. Since recent breakthrough in targeted pharmacotherapy, CFTR mutants with impaired gating are candidates for stimulation by potentiator drugs. Thus, understanding the molecular pathology of individual mutations has become important. The relatively common R117H mutation affects an extracellular loop, but nevertheless causes a strong gating defect. Here, we identify a hydrogen bond between the side chain of arginine 117 and the backbone carbonyl group of glutamate 1124 in the cryo-electronmicroscopic structure of phosphorylated, ATP-bound CFTR. We address the functional relevance of that interaction for CFTR gating using macroscopic and microscopic inside-out patch-clamp recordings. Employing thermodynamic double-mutant cycles, we systematically track gating-state-dependent changes in the strength of the R117-E1124 interaction. We find that the H-bond is formed only in the open state, but neither in the short-lived 'flickery' nor in the long-lived 'interburst' closed state. Loss of this H-bond explains the strong gating phenotype of the R117H mutant, including robustly shortened burst durations and strongly reduced intraburst open probability. The findings may help targeted potentiator design.
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