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(Reference retrieved automatically from Web of Science through information on FAPESP grant and its corresponding number as mentioned in the publication by the authors.)

Revisiting protein kinase-substrate interactions: Toward therapeutic development

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Author(s):
de Oliveira, Paulo Sergio L. [1] ; Ferraz, Felipe Augusto N. [1] ; Pena, Darlene A. [2] ; Pramio, Dimitrius T. [2] ; Morais, Felipe A. [2] ; Schechtman, Deborah [2]
Total Authors: 6
Affiliation:
[1] Ctr Nacl Pesquisa Energia & Mat, Lab Nacl Biociencias, BR-13083970 Campinas, SP - Brazil
[2] Univ Sao Paulo, Dept Bioquim, Inst Quim, BR-05508000 Sao Paulo - Brazil
Total Affiliations: 2
Document type: Review article
Source: Science Signaling; v. 9, n. 420 MAR 22 2016.
Web of Science Citations: 18
Abstract

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 nonlinearmotifs. 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. (AU)

FAPESP's process: 12/24154-4 - Specific conformational antibodies for PKC beta I and their applications
Grantee:Deborah Schechtman
Support Opportunities: Regular Research Grants
FAPESP's process: 15/17812-3 - Mecanisms of regulation of the expression of the atypical protein kinase C PKMz and identification of interacting proteins in a neuro specific context.
Grantee:Dimitrius Tansini Pramio
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 11/10321-3 - Functional characterization of protein kinase c beta 1 in self-renewal
Grantee:Darlene Aparecida Pena
Support Opportunities: Scholarships in Brazil - Doctorate
FAPESP's process: 15/21786-8 - Development, characterization and applications of PKC activation specific antibodies
Grantee:Deborah Schechtman
Support Opportunities: Regular Research Grants