Understanding tyrosine kinase domain plasticity through identification of protein residues involved in the control of the conformational transition

Diplôme Thèse Understanding tyrosine kinase domain plasticity through identification of protein residues involved in the control of the conformational transition eng 2011-03-30 author Boubeva Ralitza 604233 director Scapozza Leonardo 600318 10.13097/archive-ouverte/unige:17314 urn:nbn:ch:unige-173144 Sc. 4300 The aim of this thesis consisted in the identification of key amino acids residues governing the transition from active to inactive protein kinase domain conformation. We used the kinase domain of c-Src as a case study because of the wealth of structural information on this protein. We could demonstrate that residues governing the kinase domain dynamics of c-Src are located far from the ATP-binding site and form a network of hydrophobic interactions at the interface between the N-lobe and the C-lobe of the kinase domain. The identified amino acids and in particular Leu317 dictate the conformational plasticity of the kinase domain by influencing the rate of the DFG-flip. Furthermore, we could provide experimental evidence that the DFG-flip is the most probable molecular mechanism for the release of ADP at the end of the catalytic cycle and that both DFG-in and DFG-out conformations are present within the catalytic cycle of c-Src. Tyrosine kinase Conformational plasticity C-Src DFG-flip Dewey 615 31 Section des sciences pharmaceutiques 17 false 0f77e067-7573-4601-9622-e90adb0c9559 Thesis Public Thesis_Ralitza_Boubeva.pdf 4280150 application/pdf openAccess Faculté des sciences / Section des sciences pharmaceutiques

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Understanding tyrosine kinase domain plasticity through identification of protein residues involved in the control of the conformational transition				2011	919	1,007

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Boubeva, Ralitza