Figure 4.

Molecular simulations showing that VX-770 potentially interacts at multiple sites on CFTR in a lipid bilayer

(A) Overview of the structure of human CFTR (PDB: 6MSM) with VX-770 binding regions based on MD simulations shown in mesh representation. The ordered domains of CFTR are color coded (red: Lasso motif-MSD1; yellow: NBD1; blue: MSD2; green: NBD2). All mesh are shown in black except at photolabeling-MS identified location c which is shown in cyan. Two functional residues investigated through mutagenesis, K1041 and F1052, are shown in sphere representation as indicated.

(B) Snapshots of VX-770 bound to a protein cavity at location c. On the top, stick representations of VX-770 and neighboring protein residues are shown (heavy atom contact distance cutoff: 0.45 nm). On the bottom, surface representations of the protein cavities are shown (red: oxygen; blue: nitrogen; yellow: sulfur; gray: carbon and hydrogen). The two binding poses shown correspond to the two most favorable binding events in Figure S2-A in terms of potential energy of interaction with CFTR.