A comprehensive update of the sequence and structure classification of kinases

Background: A comprehensive update of the classification of all available kinases was carried out. This survey presents a complete global picture of this large functional class of proteins and confirms the soundness of our initial kinase classification scheme. Results: The new survey found the total number of kinase sequences in the protein database has increased more than three- fold ( from 17,310 to 59,402), and the number of determined kinase structures increased two- fold ( from 359 to 702) in the past three years. However, the framework of the original two- tier classification scheme ( in families and fold groups) remains sufficient to describe all available kinases. Overall, the kinase sequences were classified into 25 families of homologous proteins, wherein 22 families (similar to 98.8% of all sequences) for which three- dimensional structures are known fall into 10 fold groups. These fold groups not only include some of the most widely spread proteins folds, such as the Rossmann- like fold, ferredoxin- like fold, TIM- barrel fold, and antiparallel beta- barrel fold, but also all major classes ( all alpha, all beta, alpha+beta, alpha/beta) of protein structures. Fold predictions are made for remaining kinase families without a close homolog with solved structure. We also highlight two novel kinase structural folds, riboflavin kinase and dihydroxyacetone kinase, which have recently been characterized. Two protein families previously annotated as kinases are removed from the classification based on new experimental data. Conclusion: Structural annotations of all kinase families are now revealed, including fold descriptions for all globular kinases, making this the first large functional class of proteins with a comprehensive structural annotation. Potential uses for this classification include deduction of protein function, structural fold, or enzymatic mechanism of poorly studied or newly discovered kinases based on proteins in the same family.