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• W3140953492 abstract "Abstract 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." @default.
• W3140953492 created "2021-04-13" @default.
• W3140953492 creator A5025357844 @default.
• W3140953492 creator A5050778327 @default.
• W3140953492 creator A5058080897 @default.
• W3140953492 creator A5071084031 @default.
• W3140953492 date "2021-04-06" @default.
• W3140953492 modified "2023-09-23" @default.
• W3140953492 title "The Mechanism of Activation of Monomeric B-Raf V600E" @default.
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• W3140953492 doi "https://doi.org/10.1101/2021.04.06.438646" @default.
• W3140953492 hasPublicationYear "2021" @default.
• W3140953492 type Work @default.
• W3140953492 sameAs 3140953492 @default.

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