{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Baatallah N"],"funding":["association vaincre la mucoviscidose","grand équipement national de calcul intensif"],"pagination":["7813-7829"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC11071985"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["78(23)"],"pubmed_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."],"journal":["Cellular and molecular life sciences : CMLS"],"pubmed_title":["Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR."],"pmcid":["PMC11071985"],"funding_grant_id":["2019-A0060707206","RF20170502018","2018-A0040707206","2020-A0080707206","2017-A0020707206"],"pubmed_authors":["Edelman A","Baatallah N","Callebaut I","Elbahnsi A","Servel N","Sermet-Gaudelus I","Pranke I","Mornon JP","Decout JL","Chevalier B","Zelli R","Hinzpeter A"],"additional_accession":[]},"is_claimable":false,"name":"Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.","description":"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.","dates":{"release":"2021-01-01T00:00:00Z","publication":"2021 Dec","modification":"2026-06-03T04:26:44.428Z","creation":"2026-04-24T03:09:38.165Z"},"accession":"S-EPMC11071985","cross_references":{"pubmed":["34714360"],"doi":["10.1007/s00018-021-03994-5"]}}