期刊
CELLULAR AND MOLECULAR LIFE SCIENCES
卷 78, 期 23, 页码 7813-7829出版社
SPRINGER BASEL AG
DOI: 10.1007/s00018-021-03994-5
关键词
Chemical chaperone; Cystic fibrosis; Protein folding; Binding site; Molecular dynamics
资金
- GENCI-[CINES] [2017-A0020707206, 2018-A0040707206, 2019-A0060707206, 2020-A0080707206]
- French Association Vaincre la Mucoviscidose
- Association pour l'Aide a la Recherche contre la Mucoviscidose (AARM)
Protein misfolding is associated with various diseases, including cystic fibrosis. Correctors like VX-809, VX-661, and VX-445 have been developed to rescue mutant proteins; through blind docking and molecular dynamics simulations, potential binding sites and mechanisms of action have been identified. These correctors stabilize protein-lipid interfaces and enhance inter-domain assembly, providing novel insights into rescuing misfolded proteins with small molecules.
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.
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