Thermodynamic basis for CFTR activity potentiation

Trikafta modulators can correct the thermal and gating defects of the most common cystic fibrosis mutant F508del of the human cystic fibrosis transmembrane conductance regulator (hCFTR). While folding correctors VX-445 and VX-809 are sufficient to restore the Mg/ATP-dependent dimerization between the two nucleotide binding domains (NBD1 and NBD2) for channel opening, the thermodynamic basis for the activity potentiation by VX-770 in Trikafta remains unknown. Here, the thermoring structures and interdomain interactions of NBD2 were examined and compared with the counterparts of NBD1 with or without F508 in response to ligand binding. The results demonstrated that comparable thermostability between dimerized NBD1 and NBD2 was required to stabilize an activated intermediate for the channel activity potentiation by VX-770. Thus, a global induced fit across the interdomain interfaces upon ligand binding may optimize cooperative ligand-mediated NBD dimerization and improve the treatment of cystic fibrosis.