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Coarse master equations for peptide folding dynamics 总被引:1,自引:0,他引:1
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Phosphorylation of RAF Kinase Dimers Drives Conformational Changes that Facilitate Transactivation
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Dr. Pablo G. Jambrina Dr. Nora Rauch Dr. Ruth Pilkington Dr. Katja Rybakova Dr. Lan K. Nguyen Prof. Boris N. Kholodenko Dr. Nicolae‐Viorel Buchete Prof. Walter Kolch Dr. Edina Rosta 《Angewandte Chemie (International ed. in English)》2016,55(3):983-986
RAF kinases are key players in the MAPK signaling pathway and are important targets for personalized cancer therapy. RAF dimerization is part of the physiological activation mechanism, together with phosphorylation, and is known to convey resistance to RAF inhibitors. Herein, molecular dynamics simulations are used to show that phosphorylation of a key N‐terminal acidic (NtA) motif facilitates RAF dimerization by introducing several interprotomer salt bridges between the αC‐helix and charged residues upstream of the NtA motif. Additionally, we show that the R‐spine of RAF interacts with a conserved Trp residue in the vicinity of the NtA motif, connecting the active sites of two protomers and thereby modulating the cooperative interactions in the RAF dimer. Our findings provide a first structure‐based mechanism for the auto‐transactivation of RAF and could be generally applicable to other kinases, opening new pathways for overcoming dimerization‐related drug resistance. 相似文献
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