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Updated: May 16, 2026
09:59
Functional Reconstitution and Channel Activity Measurements of Purified Wildtype and Mutant CFTR Protein
Published on: March 9, 2015
The power stroke driven by ATP binding in CFTR as studied by molecular dynamics simulations
Tomoka Furukawa-Hagiya1, Tadaomi Furuta, Shuntaro Chiba
1Center for Biological Resources and Informatics, Tokyo Institute of Technology, 4259-B-62, Nagatsuta-cho, Midori-ku, Yokohama, 226-8501, Japan.
The Journal of Physical Chemistry. B
|December 11, 2012
Summary
Understanding how ATP binding opens the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) chloride channel is key. This study used molecular dynamics simulations to reveal ATP binding drives NBD dimerization and conformational changes, likely opening the ion pathway.
Area of Science:
- Biochemistry
- Molecular Biology
- Structural Biology
Background:
- Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is an ABC protein chloride channel.
- The molecular mechanism of CFTR channel gating by ATP remains unclear.
Purpose of the Study:
- To elucidate the atomic-level mechanism of CFTR channel gating.
- To investigate the role of ATP binding in CFTR conformational changes.
Main Methods:
- Constructed an atomic model of inward-facing CFTR using X-ray structures of related ABC proteins.
- Performed molecular dynamics (MD) simulations in a membrane environment.
- Utilized principal component analysis (PCA) to analyze MD trajectories.
Main Results:
- In the MgATP-bound state, NBDs formed a dimer with ATP sandwiched between motifs.
- The apo state showed a closed conformation similar to ATP-free MsbA.
- NBD dimerization induced significant structural and dynamical changes in TMDs, suggesting chloride access path formation.
Conclusions:
- ATP binding drives NBD dimerization and NBD-TMD concerted motions.
- This mechanism is crucial for CFTR chloride channel gating.
- The free energy from ATP binding powers these conformational changes.
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