The mechanism of activation of monomeric B-Raf V600E

Ryan C. Maloney, Mingzhen Zhang, Hyunbum Jang, Ruth Nussinov*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review


Oncogenic mutations in the serine/threonine kinase B-Raf, particularly the V600E mutation, are frequent in cancer, making it a major drug target. Although much is known about B-Raf's active and inactive states, questions remain about the mechanism by which the protein changes between these two states. Here, we utilize molecular dynamics to investigate both wild-type and V600E B-Raf to gain mechanistic insights into the impact of the Val to Glu mutation. The results show that the wild-type and mutant follow similar activation pathways involving an extension of the activation loop and an inward motion of the αC-helix. The V600E mutation, however, destabilizes the inactive state by disrupting hydrophobic interactions present in the wild-type structure while the active state is stabilized through the formation of a salt bridge between Glu600 and Lys507. Additionally, when the activation loop is extended, the αC-helix is able to move between an inward and outward orientation as long as the DFG motif adopts a specific orientation. In that orientation Phe595 rotates away from the αC-helix, allowing the formation of a salt bridge between Lys483 and Glu501. These mechanistic insights have implications for the development of new Raf inhibitors.

Original languageEnglish
Pages (from-to)3349-3363
Number of pages15
JournalComputational and Structural Biotechnology Journal
StatePublished - Jan 2021


  • Activation mechanism
  • B-Raf
  • Kinase
  • Oncogene
  • Protein structure


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