title: The effect of a widespread cancer-causing mutation on the inactive to active dynamics of the B-Raf kinase.
abstract: 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.
authors: Department of Chemistry, University College London, London, U.K.
authors: Kristen A
authors: KA
authors: Marino
authors: Department of Chemistry, University College London, London, U.K.
authors: Ludovico
authors: L
authors: Sutto
authors: Department of Chemistry, University College London, London, U.K.
authors: Francesco Luigi
authors: FL
authors: Gervasio
mesh_terms: D020134:Catalytic Domain; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics*; D056004:Molecular Dynamics Simulation; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D048493:Proto-Oncogene Proteins B-raf