Combining theoretical and experimental data to decipher CFTR 3D structures and functions.

Area of Science:

• Structural Biology
• Biophysics
• Molecular Medicine

Background:

• Cryo-electron microscopy (cryo-EM) has provided 3D structures of the cystic fibrosis transmembrane conductance regulator (CFTR).
• Existing cryo-EM data primarily depicts inactive CFTR states, including apo and ATP-bound closed conformations.
• Understanding the transition to active CFTR states is crucial for therapeutic development.

Purpose of the Study:

• To model the open and closed forms of the CFTR channel.
• To gain insights into the conformational transitions leading to active CFTR.
• To identify critical structural elements involved in CFTR activation and function.

Main Methods:

• Development of 3D structure models for open and closed CFTR.
• Utilizing metadynamics simulations to study conformational dynamics.
• Comparing simulation data with existing cryo-EM experimental data.

Main Results:

• 3D structure models of open and closed CFTR were generated and validated.
• Metadynamics simulations provided insights into the conformational transition mechanisms.
• Key regions, including membrane-spanning domains, NBD1, and the N-terminal extension, were identified as critical for conformational plasticity.
• Predicted conformational plasticity in NBD1 and the N-terminal extension facilitates interaction with filamin.

Conclusions:

• 3D structure models, supported by simulations and cryo-EM data, offer valuable insights into CFTR activation.
• Conformational plasticity in specific CFTR domains is essential for its transition to active states.
• These findings contribute to understanding CFTR regulation and potential therapeutic strategies for cystic fibrosis.