conservation, variability and the modeling of active protein kinases保护、可变性和活性蛋白激酶的建模.pdf

Conservation, Variability and the Modeling of Active Protein Kinases 1,2,3 4 4 1,2,3,5 James D. R. Knight , Bin Qian , David Baker , Rashmi Kothary * 1 Molecular Medicine Program, Ottawa Health Research Institute, Ottawa, Ontario, Canada, 2 The University of Ottawa Centre for Neuromuscular Disease, Ottawa, Ontario, Canada, 3 Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada, 4 Department of Biochemistry, University of Washington, Seattle, Washington, United States of America, 5 Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada The human proteome is rich with protein kinases, and this richness has made the kinase of crucial importance in initiating and maintaining cell behavior. Elucidating cell signaling networks and manipulating their components to understand and alter behavior require well designed inhibitors. These inhibitors are needed in culture to cause and study network perturbations, and the same compounds can be used as drugs to treat disease. Understanding the structural biology of protein kinases in detail, including their commonalities, differences and modes of substrate interaction, is necessary for designing high quality inhibitors that will be of true use for cell biology and disease therapy. To this end, we here report on a structural analysis of all available active-conformation protein kinases, discussing residue conservation, the novel features of such conservation, unique properties of atypical kinases and variability in the context of substrate binding. We also demonstrate how this information can be used for structure prediction. Our findings will be of use not only in understanding protein kinase function and evolution, but they highlight the flaws inherent in kinase dru