Conservation, variability and the modeling of active protein kinases

TitleConservation, variability and the modeling of active protein kinases
Publication TypeJournal Article
Year of Publication2007
AuthorsKnight, J. D. R., Qian B., Baker D., & Kothary R.
JournalPloS one
Volume2
Issue10
Paginatione982
Date Published2007
ISSN1932-6203
KeywordsAdenosine Triphosphate, Algorithms, Animals, Collaborative Publication, Computational Biology, Cyclic AMP-Dependent Protein Kinases, Humans, Models, Biological, Molecular Conformation, Protein Binding, Protein Conformation, Protein Kinases, Proteomics, Signal Transduction, Software, Substrate Specificity
Abstract

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 drug design as commonly practiced and dictate an appropriate strategy for the sophisticated design of specific inhibitors for use in the laboratory and disease therapy.

Alternate JournalPLoS ONE
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