1.

Thermoring structures of phosphorylated hCFTR/E1371Q/ΔF508 with VX-445 and VX-809 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/ΔF508 with VX-445 and VX-809 bound in the presence of Mg/ATP/PKA at 4 °C (PDB ID, 8EIO, 2.8 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 Y517–D537 H-bond in the biggest Grid₁₀ is highlighted. The total grid sizes and the total grid size-controlled noncovalent interactions along the single peptide chain of NBD1 from L383 to L636 are shown in cyan and black circles, respectively. (b) Noncovalent interactions at the NBD1/ICL4 interface (Y380 is at the TMD1–NBD1 linker). (c) The structure of the biggest Grid₁₀ with a 10-residue size to control the least-stable Y517–D537 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 biggest Grid₁₀ to control the least-stable Y517–D537 H-bond in the blue box.