Extended Data Fig. 8: BRAF inhibitors that are “Paradox busters” disrupt BRAF dimers by causing steric clash at the dimer interface.
From: Negative regulation of RAF kinase activity by ATP is overcome by 14-3-3-induced dimerization
BRAFKD dimer (yellow) overlaid with two PLX-4720 bound BRAFKD monomers (PDB code 4WO5) (blue), aligned by their C-lobes. While most of the N-lobe and C-lobe regions overlay well, PLX4720 induces a large shift of the aC helix, causing a steric clash at the dimer interface, destabilizing the dimer interface. This is likely the mechanism of the current series of “paradox buster” molecules. With PLX4720, this shift can be accommodated in a BRAF dimer, however this requires slight conformational changes at the dimer interface and in the binding orientation of one of two bound PLX4720 molecules (PDB code 3C4C).
