ArticleCellular and molecular life sciences : CMLS2021
Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.
Article in Cellular and molecular life sciences : CMLS, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 33 papers.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
33 citing papers in PubMed.
- Alpha-methyl-para-tyrosine and amphetamine ameliorate hyperactivity in a novel mouse model of dopamine transporter deficiency syndrome.EMBO molecular medicine · 2026Article
- Chronic and acute modulator treatment restore wild-type-like activity and stability to the primary cystic fibrosis-causingProceedings of the National Academy of Sciences of the United States of America · 2026Article
- The response of rare CFTR mutations to specific modulator combinations.ERJ open research · 2025Article
- Correction of a Traffic-Defective Missense ABCB11 Variant Responsible for Progressive Familial Intrahepatic Cholestasis Type 2.International journal of molecular sciences · 2025Article
- Global functional genomics reveals GRK5 as a cystic fibrosis therapeutic target synergistic with current modulators.iScience · 2025Article
- Target Identification with Live-Cell Photoaffinity Labeling and Mechanism of Action Elucidation of ARN23765, a Highly Potent CFTR Corrector.Journal of medicinal chemistry · 2025Article
- Unraveling the Mechanism of Action, Binding Sites, and Therapeutic Advances of CFTR Modulators: A Narrative Review.Current issues in molecular biology · 2025Review
- ATP-Binding Cassette and Solute Carrier Transporters: Understanding Their Mechanisms and Drug Modulation Through Structural and Modeling Approaches.Pharmaceuticals (Basel, Switzerland) · 2024Review
- A uniquely efficacious type of CFTR corrector with complementary mode of action.Science advances · 2024Article
- Organic Synthesis and Current Understanding of the Mechanisms of CFTR Modulator Drugs Ivacaftor, Tezacaftor, and Elexacaftor.Molecules (Basel, Switzerland) · 2024Review
- Benchmarking AlphaMissense Pathogenicity Predictions Against Cystic Fibrosis Variants.bioRxiv : the preprint server for biology · 2024Article
- Benchmarking AlphaMissense pathogenicity predictions against cystic fibrosis variants.PloS one · 2024Article
- CFTR Modulators: From Mechanism to Targeted Therapeutics.Handbook of experimental pharmacology · 2024Article
- Folding correctors can restore CFTR posttranslational folding landscape by allosteric domain-domain coupling.Nature communications · 2023Article
- CFTR Folding: From Structure and Proteostasis to Cystic Fibrosis Personalized Medicine.ACS chemical biology · 2023Review
- Computational Exploration of Potential CFTR Binding Sites for Type I Corrector Drugs.Biochemistry · 2023Article
- Rescue of Rare CFTR Trafficking Mutants Highlights a Structural Location-Dependent Pattern for Correction.International journal of molecular sciences · 2023Article
- Acting on the CFTR Membrane-Spanning Domains Interface Rescues Some Misfolded Mutants.International journal of molecular sciences · 2022Article
- Redefining Hypo- and Hyper-Responding Phenotypes of CFTR Mutants for Understanding and Therapy.International journal of molecular sciences · 2022Article
- Pyrazole-containing pharmaceuticals: target, pharmacological activity, and their SAR studies.RSC medicinal chemistry · 2022Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
12 authors.
Funding
Abstract
Protein misfolding is involved in a large number of diseases, among which cystic fibrosis. Complex intra- and inter-domain folding defects associated with mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, among which p.Phe508del (F508del), have recently become a therapeutical target. Clinically approved correctors such as VX-809, VX-661, and VX-445, rescue mutant protein. However, their binding sites and mechanisms of action are still incompletely understood. Blind docking onto the 3D structures of both the first membrane-spanning domain (MSD1) and the first nucleotide-binding domain (NBD1), followed by molecular dynamics simulations, revealed the presence of two potential VX-809 corrector binding sites which, when mutated, abrogated rescue. Network of amino acids in the lasso helix 2 and the intracellular loops ICL1 and ICL4 allosterically coupled MSD1 and NBD1. Corrector VX-445 also occupied two potential binding sites on MSD1 and NBD1, the latter being shared with VX-809. Binding of both correctors on MSD1 enhanced the allostery between MSD1 and NBD1, hence the increased efficacy of the corrector combination. These correctors improve both intra-domain folding by stabilizing fragile protein-lipid interfaces and inter-domain assembly via distant allosteric couplings. These results provide novel mechanistic insights into the rescue of misfolded proteins by small molecules.
Indexed as
Identifiers
What OpenQuestion holds
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.