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Pharmacological cha...
Pharmacological chaperones improve intra-domain stability and inter-domain assembly via distinct binding sites to rescue misfolded CFTR
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Baatallah, N. (författare)
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- Elbahnsi, Ahmad (författare)
- KTH,Tillämpad fysik,Science for Life Laboratory, SciLifeLab,Sorbonne Université, Muséum National d’Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC, Paris, 75005, France
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Mornon, J. -P (författare)
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Chevalier, B. (författare)
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Pranke, I. (författare)
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Servel, N. (författare)
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Zelli, R. (författare)
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Décout, J. -L (författare)
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Edelman, A. (författare)
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Sermet-Gaudelus, I. (författare)
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Callebaut, I. (författare)
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Hinzpeter, A. (författare)
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(creator_code:org_t)
- 2021-10-29
- 2021
- Engelska.
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Ingår i: Cellular and Molecular Life Sciences (CMLS). - : Springer Nature. - 1420-682X .- 1420-9071. ; 78:23, s. 7813-7829
- Relaterad länk:
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https://urn.kb.se/re...
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https://doi.org/10.1...
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Abstract
Ämnesord
Stäng
- 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.
Ämnesord
- NATURVETENSKAP -- Biologi -- Mikrobiologi (hsv//swe)
- NATURAL SCIENCES -- Biological Sciences -- Microbiology (hsv//eng)
Nyckelord
- Binding site
- Chemical chaperone
- Cystic fibrosis
- Molecular dynamics
- Protein folding
Publikations- och innehållstyp
- ref (ämneskategori)
- art (ämneskategori)
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Till lärosätets databas
- Av författaren/redakt...
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Baatallah, N.
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Elbahnsi, Ahmad
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Mornon, J. -P
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Chevalier, B.
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Pranke, I.
-
Servel, N.
-
visa fler...
-
Zelli, R.
-
Décout, J. -L
-
Edelman, A.
-
Sermet-Gaudelus, ...
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Callebaut, I.
-
Hinzpeter, A.
-
visa färre...
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- NATURVETENSKAP
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NATURVETENSKAP
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och Biologi
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och Mikrobiologi
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Cellular and Mol ...
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