Fig. 2: Structural analysis of BRAFV600E bound to Ponatinib (PON).
a Crystal structure of the BRAFV600E/PON protomer structure. BRAFV600E structure depicted in ribbons (gray) showing the αC-helix (green). The partially disordered activation loop (orange) is shown in a tube representation. PON is shown in sticks and molecular surface (yellow). b Fo – Fc electron density of PON in the BRAFV600E/PON complex contoured at 3σ. c Close-up of PON binding (in ball-and-sticks) to its binding pocket (transparent surface) in BRAFV600E. Protein sub-pockets recognizing various inhibitor moieties are colored, including the allosteric pocket (green). d A close-up view of PON binding interactions with BRAFV600E. PON is shown in ball-and-sticks and BRAFV600E in a cartoon model. Protein residues interacting with PON are shown in sticks. Note hydrogen bond interactions of PON with the backbone of residues H574 and I573 in the allosteric site and interaction with the D594 and F595 of the DFG motif and catalytic E501 of the αC-helix. A structural water molecule in the binding site (W1) is shown as a sphere. H-bonds are shown in dashed lines. e A superposition of BRAF type-II/αC-IN inhibitors LY3009120 (LY, green, PDB 5C9C), TAK-632 (TAK, orange, PDB 4KSP), and AZ-628 (AZ, blue, PDB 4G9R) bound in their BRAF recognition pockets with PON in BRAFV600E/PON structure. Protein parts were omitted from clarity. f A superposition of BRAF type-Ib/αC-OUT inhibitors Vemurafenib (VEM, cyan, PDB 3OG7) and Dabrafenib (DAB, orange, PDB 4XV2) bound in their BRAF recognition pockets with PON in BRAFV600E/PON structure. Inhibitors are depicted in sticks and proteins in a cartoon model.
