2.

Thermoring structures of phosphorylated hCFTR/E1371Q with VX-770 bound in the activated state at 4 °C. (a) The grid-like noncovalently interacting mesh network based on the cryo-EM structure of hCFTR/E1371Q in the presence of Mg/ATP/PKA and VX-770 at 4 °C (PDB ID, 6O2P, 3.3 Å). Salt bridges, H-bonds, and π interactions are colored purple, orange, and green, respectively. The constrained grid sizes required to control the least-stable noncovalent interactions in the grids are labeled with black numbers. The least-stable Q525–E585 H-bond in the second biggest Grid₈ is highlighted. The total grid sizes and the total grid size-controlled noncovalent interactions along the single peptide chain of NBD1 from E384 to Q637 are shown in cyan and black circles, respectively. (b) Noncovalent interactions at the NBD1/ICL4 interface. (c) The structure of the second biggest Grid₈ with an 8-residue size to control the least-stable Q525–E585 H-bond. The grid size and the equivalent basic H-bonds for the least-stable noncovalent interaction are shown in and near a red circle. (d) The sequence of the second biggest Grid₈ to control the least-stable Q525–E585 H-bond in the blue boxes.