4MNE

Biomarker development concept

G-573 , an ATP-uncompetitive inhibitor of MEK1

4MNE

While G-573 and ACP are not necessary for formation of a tetrameric or dimeric BRAF^KD-MEK1 complex in solution , inclusion of G-573 stabilizes the complex in a preactivation-like state through specific interactions with the MEK1 activation loop. G-573 forms numerous interactions with MEK1 including a hydrogen bond with the amide backbone of S212 in the AS such that MEK1 residues S218 and S222 are not accessible for phosphorylation by BRAF . In the absence of this inhibitor, the MEK1 activation loop is likely sufficiently flexible to access the active site of BRAF without disruption of the rest of the interface. Phosphorylation at S218 and S222 following incubation of RAF and MEK1 with ATP may result in dissociation of RAF^KD-MEK1 complexes due to the steric and electrostatic effects of phosphorylation. Binding of a nucleotide analog alone (AMP-PCP) in the absence of a MEK inhibitor has no effect on complex formation

Biochemical scheme with interaction of wild-type BRAF and MEK proteins

G-573 , an ATP-uncompetitive inhibitor of MEK1

Adenosine triphosphate, an organic chemical used for driving biological processes

The BRAF^KD-MEK1 interface is formed by both the β-rich N lobes and the predominantly α-helical C lobes, yielding a high affinity interaction (K_D ∼43 nM) with critical contacts between the activation segments (AS) of the two proteins

MEK

BRAF

PDB:4MNE

Fig. 1. Crystal Structure of Wild Type BRAF- MEK

number condition
4.2758676571

max eigenvalue
3.126989e-19

min eigenvalue
1.65675e-23

error computational SVD
1.9874037e-19

4MNE (wt)

Figure 2: Dependence of RMSD(root-mean-square deviation) on the configuration number

The fig.2 shows a rapidly oscillating character, which indicates the impossibility of finding a local minimum: optimization completed because at the initial point, the objective function is nondecreasing in feasible directions. As follows from the fig.1 the local minimum no found.

Dependence of RMSD(root-mean-square deviation) on the configuration number.

G-573 is an allosteric inhibitor of MEK that is both potent and selective.

G-573