Fig. 2.
Depiction of the three-dimensional structure of PLX4720 bound to B-Raf. (A) The structure of B-RafV600E bound to PLX4720 (yellow) is overlayed with an ATP model based on structures of ATP analogs in complex with other tyrosine kinases (orange). This view indicates that the PLX4720 scaffold overlaps with the adenine-binding site, but the tail of PLX4720 binds to a different pocket from the ATP ribose-triphosphate tail. The positions of the hinge, activation loop (A-loop), and phosphate-binding loop (P-loop) are also shown. (B) A surface representation shows PLX4720 binding to the B-Raf-selective pocket in the active conformation. (C) A surface representation shows PLX4720 binding to the kinase general pocket in the inactive conformation. (D) A close-up view shows the overlay PLX4720 bound to both active (green) and inactive (purple) conformations of the V600 protein, and PLX3203 (yellow) bound to V600E protein in the active kinase conformation. (E) A stereoview shows the specific interactions of PLX4720 to the active kinase conformation. In this conformation, the phenylalanine of the DFG loop is pointing in toward the compound-binding site. (F) A stereoview shows the specific interactions of PLX4720 to the inactive kinase conformation. In this conformation, the phenylalanine of the DFG loop is pointing away from the compound-binding site, and binding of PLX4720 is disfavored, leading to partial occupancy of this site even at the 1 mM compound concentration used in cocrystallography.