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TitleMechanism of CFTR correction by type I folding correctors.
Journal, issue, pagesCell, Vol. 185, Issue 1, Page 158-168.e11, Year 2022
Publish dateJan 6, 2022
AuthorsKarol Fiedorczuk / Jue Chen /
PubMed AbstractSmall 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 ...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.
External linksCell / PubMed:34995514
MethodsEM (single particle)
Resolution2.7 - 3.9 Å
Structure data

25445

7sv7

EMDB-25445, PDB-7sv7:
The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Tezacaftor (VX-661)
Method: EM (single particle) / Resolution: 3.8 Å

25447

7svd

EMDB-25447, PDB-7svd:
The complex of phosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) with ATP/Mg and Lumacaftor (VX-809)
Method: EM (single particle) / Resolution: 2.7 Å

25452

7svr

EMDB-25452, PDB-7svr:
The complex of dephosphorylated human cystic fibrosis transmembrane conductance regulator (CFTR) and Lumacaftor (VX-809)
Method: EM (single particle) / Resolution: 3.9 Å

Chemicals

ChemComp-MG:
Unknown entry

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM / Adenosine triphosphate

ChemComp-DD9:
nonane / Nonane

ChemComp-D12:
DODECANE / Dodecane

ChemComp-CLR:
CHOLESTEROL / Cholesterol

ChemComp-C14:
TETRADECANE / Tetradecane

ChemComp-PJ8:
heptadecane / Heptadecane

ChemComp-CV6:
Tezacaftor / Tezacaftor

ChemComp-D10:
DECANE / Decane

ChemComp-VX8:
Lumacaftor / Lumacaftor

ChemComp-UNX:
Unknown entry

ChemComp-HOH:
WATER / Water

Source
  • homo sapiens (human)
KeywordsATP-BINDING PROTEIN / ABC transporter / ion channel / folding correction / MEMBRANE PROTEIN

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