期刊
NATURE CHEMICAL BIOLOGY
卷 9, 期 7, 页码 444-U69出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/NCHEMBIO.1253
关键词
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资金
- Dutch Cystic Fibrosis foundation
- Wilhelmina Children's Hospital Research fund
- Hungarian National Science Foundation [MB08C-80039]
- European Union [FP7-IRG 239270]
- European Research Area (ERA)Chemistry Hungarian Scientific Research Fund (OTKA) [102166]
- Tara K. Telford Fund for Cystic Fibrosis Research at the University of California-Davis
- US National Institutes of Health (NIH) [DK072517, GM089153]
- NIH-National Institute of Diabetes and Digestive and Kidney Diseases [R01DK75302]
- CFFT Inc.
- Cystic Fibrosis Canada
- Canadian Institutes of Health Research
- Canada Foundation for Innovation
- European Molecular Biology Association
- Fonds de Recherche Sante Quebec Fellowship
- Grants-in-Aid for Scientific Research [25893275] Funding Source: KAKEN
The most common cystic fibrosis mutation, Delta F508 in nucleotide binding domain 1 (NBD1), impairs cystic fibrosis transmembrane conductance regulator (CFTR)-coupled domain folding, plasma membrane expression, function and stability. VX-809, a promising investigational corrector of Delta F508-CFTR misprocessing, has limited clinical benefit and an incompletely understood mechanism, hampering drug development. Given the effect of second-site suppressor mutations, robust Delta F508-CFTR correction most likely requires stabilization of NBD1 energetics and the interface between membrane-spanning domains (MSDs) and NBD1, which are both established primary conformational defects. Here we elucidate the molecular targets of available correctors: class I stabilizes the NBD1-MSD1 and NBD1-MSD2 interfaces, and class II targets NBD2. Only chemical chaperones, surrogates of class III correctors, stabilize human Delta F508-NBD1. Although VX-809 can correct missense mutations primarily destabilizing the NBD1-MSD1/2 interface, functional plasma membrane expression of Delta F508-CFTR also requires compounds that counteract the NBD1 and NBD2 stability defects in cystic fibrosis bronchial epithelial cells and intestinal organoids. Thus, the combination of structure-guided correctors represents an effective approach for cystic fibrosis therapy.
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