Kinase proteins play a fundamental role in cellular signaling: by transferring a phosphate group from ATP to specific target molecules they are able to modify their activity and consequently regulate cell function. Given the importance of kinases in regulating most of the cellular responses, it is not surprising that aberrant activation of kinases is one of the major causes of human diseases, including cancer, making them fundamental targets for drug design.  Conformational transitions play a central role in kinase regulation.  X-ray structures have shown that kinases adopt an active state that is maximally active and one or more inactive states that show minimal activity.The V600E mutation of B-Raf is one of the most common in metastatic melanomas.  This mutation is expected to shift the balance between the active and inactive forms of the kinase towards the former.  Thus B-Raf appears to be a promising target in the treatment of melanoma.  Complicating drug design efforts, some ATP-competitive B-Raf inhibitors induce a �paradoxical activation� of the Raf pathway.  From experimental evidence it has been deduced that drug binding promotes dimerization, and that when a drug-bound monomer dimerizes with an apo-monomer, the apo-monomer adopts an active conformation.  Unfortunately, a clear picture of B-Raf dimerization and allosteric communication within the dimer are lacking.  Using all-atom molecular dynamics simulations, we can identify the effect of the V600E mutation and drug binding on the allosteric networks within the dimer, which is difficult to obtain experimentally.  This knowledge could greatly contribute to the development of more effective and selective drugs and to counter the emergence of resistance to drugs currently in clinical use.

Allosteric communication within the B-Raf dimer: The effect of the V600E mutation and inhibitor binding

248th National Meeting (2014)

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