{"entity": "researcher", "timestamp": "2026-09-03T05:17:09.627Z", "family": "Hinzpeter", "given": "Alexandre", "initials": "A", "orcid": "0000-0001-6920-7761", "affiliations": ["INSERM, U1151, Institut Necker Enfants Malades, INEM, Paris, France. alexandre.hinzpeter@inserm.fr.", "CNRS UMR 8253 - Facult\u00e9 de M\u00e9decine, Universit\u00e9 de Paris, Paris, France. alexandre.hinzpeter@inserm.fr."], "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/researcher/0819e14817ef47189497643b49b36139.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/researcher/0819e14817ef47189497643b49b36139"}}, "publications": [{"entity": "publication", "iuid": "5bbfae6c6ac34895adcb9142cecc02db", "links": {"self": {"href": "https://publications-affiliated.scilifelab.se/publication/5bbfae6c6ac34895adcb9142cecc02db.json"}, "display": {"href": "https://publications-affiliated.scilifelab.se/publication/5bbfae6c6ac34895adcb9142cecc02db"}}, "title": "Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR.", "authors": [{"family": "Baatallah", "given": "Nesrine", "initials": "N"}, {"family": "Elbahnsi", "given": "Ahmad", "initials": "A"}, {"family": "Mornon", "given": "Jean-Paul", "initials": "JP"}, {"family": "Chevalier", "given": "Benoit", "initials": "B"}, {"family": "Pranke", "given": "Iwona", "initials": "I"}, {"family": "Servel", "given": "Nathalie", "initials": "N"}, {"family": "Zelli", "given": "Renaud", "initials": "R"}, {"family": "D\u00e9cout", "given": "Jean-Luc", "initials": "JL"}, {"family": "Edelman", "given": "Aleksander", "initials": "A"}, {"family": "Sermet-Gaudelus", "given": "Isabelle", "initials": "I"}, {"family": "Callebaut", "given": "Isabelle", "initials": "I"}, {"family": "Hinzpeter", "given": "Alexandre", "initials": "A", "orcid": "0000-0001-6920-7761", "researcher": {"href": "https://publications-affiliated.scilifelab.se/researcher/0819e14817ef47189497643b49b36139.json"}}], "type": "journal article", "published": "2021-12-00", "journal": {"title": "Cell. Mol. Life Sci.", "issn": "1420-9071", "volume": "78", "issue": "23", "pages": "7813-7829", "issn-l": "1420-682X"}, "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.", "doi": "10.1007/s00018-021-03994-5", "pmid": "34714360", "labels": [], "xrefs": [{"db": "pmc", "key": "PMC11071985"}, {"db": "pii", "key": "10.1007/s00018-021-03994-5"}], "notes": [], "created": "2026-08-21T11:05:18.406Z", "modified": "2026-08-21T11:05:18.486Z"}]}