Computational evaluation of mechanisms of kinases and related proteins

Author(s)

Raphael Vinicius Rodrigues Dias

• Document type: Master's Dissertation
• Press: São José do Rio Preto. 2018-05-28.
• Institution: Universidade Estadual Paulista (Unesp). Instituto de Biociências Letras e Ciências Exatas. São José do Rio Preto
• Defense date: 2018-04-26
• Advisor: Leandro Cristante Oliveira; Fernando Alves Melo

Abstract

The Carboxyl-terminal Src Kinase (Csk) is a protein that plays an essential role for the down-regulation of Src kinase family proteins (SFKs). When Csk presents malfunction on its regulation action, several diseases can occurs, like deformations during the fetal develop, mama, prostate, pancreas, colon cancers, as well leukemia and lymphomas. Csk presents a high sequence homology with other SFK members, but without a similar arrangement of domains. Yet, the Csk lacks a tyrosine tail, so it cannot auto-phosphorylate, but it can phosphorylate their family members. Surprisingly, the crystallography structure of Csk presents two distinct conformations classified as active and inactive. The main objective of this work is to construct a model to evaluate transitions and possible mechanisms involving Csk, making a link between conformational changes and its action. On the other hand, the adaptor protein Growth factor Receptor-Bound protein 2 (Grb2) is related to the universe of protein regulators linked to the proteins kinase as the Fibroblast Growth Factor Receptor 2 (FGFR2), being an important target for study. The set kinase and adaptor proteins is important for signaling processes involving cell proliferation, differentiation and apoptosis. Thus, Grb2 is an potential aim for the evaluation of interactions with small anticarcinogen molecules as 1,2-benzopyrone Coumarin and 2',3,4',5,7-pentahydroxyflavon Morin. In vitro essays verified the interaction between the Grb2-coumarin and Grb2-morin complexes. Thus, the second part of this work investigate the spatial location for the docking of the Coumarin and Morin into Grb2 and evaluate their interactions. (AU)

• FAPESP's process: 16/08753-6 - Evaluating kinase mechanisms and related proteins
• Grantee: Raphael Vinicius Rodrigues Dias
• Support Opportunities: Scholarships in Brazil - Master