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Structural Comparative Modeling of Multi-Domain F508del CFTR
Eli Fritz McDonald1,2, Hope Woods2,3, Shannon T Smith2,3
1Department of Chemistry, Vanderbilt University, Nashville, TN 37235, USA.
Biomolecules
|March 25, 2022
Summary
Structural models reveal how the common F508del mutation destabilizes cystic fibrosis transmembrane conductance regulator (CFTR) protein. These models also show how VX-809 corrector drugs stabilize F508del CFTR, aiding new drug design for cystic fibrosis.
Area of Science:
- Biochemistry
- Structural Biology
- Genetics
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) protein.
- The most common mutation, F508del, leads to a non-functional CFTR protein, causing mucus buildup and respiratory issues.
- Existing CF therapies target F508del CFTR, but its multi-domain structure remains poorly understood.
Purpose of the Study:
- To generate multi-domain structural models of wild-type (WT) and F508del CFTR.
- To investigate the structural impact of the F508del mutation on CFTR stability.
- To model the interaction of F508del CFTR with the corrector drug VX-809.
Main Methods:
- Utilized cryo-electron microscopy (cryo-EM) density data.
- Employed Rosetta comparative modeling (RosettaCM) for structural predictions.
- Validated models using published experimental data on CFTR NBD1 thermodynamics.
Main Results:
- Generated multi-domain structural models for WT and F508del CFTR in both inactive and active states.
- Demonstrated that the F508del mutation destabilizes the NBD1 domain and the NBD1/TMD interface.
- Revealed that VX-809 binding stabilizes multi-domain models of F508del CFTR.
Conclusions:
- The F508del mutation significantly impacts CFTR structure and stability.
- VX-809 demonstrates a stabilizing effect on F508del CFTR, providing a structural basis for its therapeutic action.
- These models offer a foundation for the rational design of novel CFTR-targeting drugs.
