ja5b01421_si_001.pdf (4.09 MB)
Download file

The Effect of a Widespread Cancer-Causing Mutation on the Inactive to Active Dynamics of the B‑Raf Kinase

Download (4.09 MB)
journal contribution
posted on 17.12.2015, 08:02 authored by Kristen A. Marino, Ludovico Sutto, Francesco Luigi Gervasio
Protein kinases play a key role in regulating cellular processes. Kinase dysfunction can lead to disease, making them an attractive target for drug design. The B-Raf kinase is a key target for the treatment of melanoma since a single mutation (V600E) is found in more than 50% of all malignant melanomas. Despite the importance of B-Raf in melanoma treatment, the molecular mechanism by which the mutation increases kinase activity remains elusive. Since kinases are tightly regulated by a conformational transition between an active and inactive state, which is difficult to capture experimentally, large-scale enhanced-sampling simulations are performed to examine the mechanism by which the V600E mutation enhances the activity of the B-Raf monomer. The results reveal that the mutation has a twofold effect. First, the mutation increases the barrier of the active to inactive transition trapping B-Raf in the active state. The mutation also increases the flexibility of the activation loop which might speed-up the rate-limiting step of phosphorylation. Both effects can be explained by the formation of salt-bridges with the Glu600 residue.

History