Trikafta restores thermodynamic coupling between two nucleotide binding domains for potentiating CFTR activity

Area of Science:

• Biochemistry
• Molecular Biology
• Computational Biophysics

Background:

• Cystic fibrosis is caused by mutations in the human cystic fibrosis transmembrane conductance regulator (CFTR) protein.
• The most common mutation, F508del-CFTR, leads to folding, thermal, and gating defects.
• Trikafta (elexacaftor/tezacaftor/ivacaftor) is a modulator therapy that addresses these defects.

Purpose of the Study:

• To investigate the thermodynamic basis for VX-770's activity potentiation in Trikafta.
• To compare the structures and interdomain interactions of NBD1 and NBD2 in the F508del mutant.
• To understand the requirements for stabilizing the activated intermediate of CFTR.

Main Methods:

• Computational study using molecular dynamics simulations.
• Analysis of thermostability and interdomain interactions of NBD1 and NBD2.
• Examination of ligand and modulator binding effects.

Main Results:

• Comparable thermostability between dimerized NBD1 and NBD2 is necessary for VX-770's potentiation.
• Ligand and modulator binding influence the interdomain interactions and stability.
• A global induced fit across interdomain interfaces is required for gating rescue.

Conclusions:

• Trikafta modulators require tight coupling between dimerized NBD1 and NBD2 for effective gating rescue.
• Achieving comparable thermostability in both nucleotide-binding domains is key to CFTR channel potentiation.
• This study elucidates the thermodynamic mechanisms underlying Trikafta's efficacy in F508del-CFTR.