Mechanism of CFTR correction by type I folding correctors.
Cell
; 185(1): 158-168.e11, 2022 01 06.
Article
en En
| MEDLINE
| ID: mdl-34995514
ABSTRACT
Small molecule chaperones have been exploited as therapeutics for the hundreds of diseases caused by protein misfolding. The most successful examples are the CFTR correctors, which transformed cystic fibrosis therapy. These molecules revert folding defects of the ΔF508 mutant and are widely used to treat patients. To investigate the molecular mechanism of their action, we determined cryo-electron microscopy structures of CFTR in complex with the FDA-approved correctors lumacaftor or tezacaftor. Both drugs insert into a hydrophobic pocket in the first transmembrane domain (TMD1), linking together four helices that are thermodynamically unstable. Mutating residues at the binding site rendered ΔF508-CFTR insensitive to lumacaftor and tezacaftor, underscoring the functional significance of the structural discovery. These results support a mechanism in which the correctors stabilize TMD1 at an early stage of biogenesis, prevent its premature degradation, and thereby allosterically rescuing many disease-causing mutations.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pliegue de Proteína
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Regulador de Conductancia de Transmembrana de Fibrosis Quística
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Benzodioxoles
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Aminopiridinas
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Indoles
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Cell
Año:
2022
Tipo del documento:
Article
País de afiliación:
Estados Unidos