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-Structure paper
タイトル | Mechanism of CFTR correction by type I folding correctors. |
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ジャーナル・号・ページ | Cell, Vol. 185, Issue 1, Page 158-168.e11, Year 2022 |
掲載日 | 2022年1月6日 |
著者 | Karol Fiedorczuk / Jue Chen / |
PubMed 要旨 | 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 ...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. |
リンク | Cell / PubMed:34995514 |
手法 | EM (単粒子) |
解像度 | 2.7 - 3.9 Å |
構造データ | EMDB-25445, PDB-7sv7: EMDB-25447, PDB-7svd: EMDB-25452, PDB-7svr: |
化合物 | ChemComp-MG: ChemComp-ATP: ChemComp-DD9: ChemComp-D12: ChemComp-CLR: ChemComp-C14: ChemComp-PJ8: ChemComp-CV6: ChemComp-D10: ChemComp-VX8: ChemComp-UNX: ChemComp-HOH: |
由来 |
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キーワード | ATP-BINDING PROTEIN / ABC transporter / ion channel / folding correction / MEMBRANE PROTEIN |