动作(物理)
类型(生物学)
预测-校正方法
医学
计算机科学
计算生物学
数学
物理
生物
应用数学
生态学
量子力学
作者
Valentina Marchesin,Lucile Monnier,Peter Blattmann,Florent Chevillard,Charles Kuntz,Camille Forny,Jörg Kämper,R. O. Studer,Alexandre Bossu,Eric A. Ertel,Oliver Nayler,Christine Brotschi,Jodi T. Williams,John Gatfield
出处
期刊:Science Advances
[American Association for the Advancement of Science (AAAS)]
日期:2024-03-01
卷期号:10 (9)
标识
DOI:10.1126/sciadv.adk1814
摘要
Three distinct pharmacological corrector types (I, II, III) with different binding sites and additive behavior only partially rescue the F508del-cystic fibrosis transmembrane conductance regulator (CFTR) folding and trafficking defect observed in cystic fibrosis. We describe uniquely effective, macrocyclic CFTR correctors that were additive to the known corrector types, exerting a complementary “type IV” corrector mechanism. Macrocycles achieved wild-type–like folding efficiency of F508del-CFTR at the endoplasmic reticulum and normalized CFTR currents in reconstituted patient-derived bronchial epithelium. Using photo-activatable macrocycles, docking studies and site-directed mutagenesis a highly probable binding site and pose for type IV correctors was identified in a cavity between lasso helix-1 (Lh1) and transmembrane helix-1 of membrane spanning domain (MSD)-1, distinct from the known corrector binding sites. Since only F508del-CFTR fragments spanning from Lh1 until MSD2 responded to type IV correctors, these likely promote cotranslational assembly of Lh1, MSD1, and MSD2. Previously corrector-resistant CFTR folding mutants were also robustly rescued, suggesting substantial therapeutic potential for type IV correctors.
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