|
Figure 2.
Depiction of the three-dimensional structure of PLX4720 bound
to B-Raf. (A) The structure of B-Raf^V600E 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.
|
