Revisiting protein kinase–substrate interactions: toward therapeutic development
| Autor: | Paulo S. L. Oliveira, Felipe Augusto Nunes Ferraz, Darlene Aparecida Pena, Dimitrius T. Pramio, Felipe Alves Morais, Deborah Schechtman |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Amino Acid Motifs Biology Biochemistry Substrate Specificity 03 medical and health sciences Structure-Activity Relationship 0302 clinical medicine Drug Delivery Systems Structure–activity relationship Animals Humans Protein phosphorylation Binding site Protein kinase A Molecular Biology Protein Kinase Inhibitors Kinase Linear sequence Computational Biology Cell Biology Cell biology 030104 developmental biology Drug development Phosphorylation BIOQUÍMICA Protein Kinases 030217 neurology & neurosurgery |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | Despite the efforts of pharmaceutical companies to develop specific kinase modulators, few drugs targeting kinases have been completely successful in the clinic. This is primarily due to the conserved nature of kinases, especially in the catalytic domains. Consequently, many currently available inhibitors lack sufficient selectivity for effective clinical application. Kinases phosphorylate their substrates to modulate their activity. One of the important steps in the catalytic reaction of protein phosphorylation is the correct positioning of the target residue within the catalytic site. This positioning is mediated by several regions in the substrate binding site, which is typically a shallow crevice that has critical subpockets that anchor and orient the substrate. The structural characterization of this protein-protein interaction can aid in the elucidation of the roles of distinct kinases in different cellular processes, the identification of substrates, and the development of specific inhibitors. Because the region of the substrate that is recognized by the kinase can be part of a linear consensus motif or a nonlinear motif, advances in technology beyond simple linear sequence scanning for consensus motifs were needed. Cost-effective bioinformatics tools are already frequently used to predict kinase-substrate interactions for linear consensus motifs, and new tools based on the structural data of these interactions improve the accuracy of these predictions and enable the identification of phosphorylation sites within nonlinear motifs. In this Review, we revisit kinase-substrate interactions and discuss the various approaches that can be used to identify them and analyze their binding structures for targeted drug development. |
| Databáze: | OpenAIRE |
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