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Development of the first model of a phosphorylated, ATP/Mg 2+ -containing B-Raf monomer by molecular dynamics simulations: a tool for structure-based design.
- Source :
-
Physical chemistry chemical physics : PCCP [Phys Chem Chem Phys] 2017 Nov 29; Vol. 19 (46), pp. 31177-31185. - Publication Year :
- 2017
-
Abstract
- A model of phosphorylated and ATP-containing B-Raf protein kinase is needed as a tool for the structure-based design of new allosteric inhibitors, since no crystal structure of such a system has been resolved. Here, we present the development of such a model as well as a thorough analysis of its structural features. This model was prepared using a systematic molecular dynamics approach considering the presence or absence of both the phosphate group at the Thr599 site and the ATP molecule. Then, different structural features (i.e. DFG motif, Mg <superscript>2+</superscript> binding loop, activation loop, phosphorylation site and αC-helix region) were analysed for each trajectory to validate the aimed 2pBRAF&#95;ATP model. Moreover, the structure and activating interactions of this 2pBRAF&#95;ATP model were found to be in agreement with previously reported information. Finally, the model was further validated by means of a molecular docking study with our previously developed lead compound I confirming that this ATP-containing, phosphorylated protein model is suitable for further structure-based design studies.
Details
- Language :
- English
- ISSN :
- 1463-9084
- Volume :
- 19
- Issue :
- 46
- Database :
- MEDLINE
- Journal :
- Physical chemistry chemical physics : PCCP
- Publication Type :
- Academic Journal
- Accession number :
- 29139502
- Full Text :
- https://doi.org/10.1039/c7cp05038k