Show simple item record

dc.contributor.authorDixit, Anshuman
dc.contributor.authorVerkhivker, Gennady M.
dc.date.accessioned2014-03-18T18:02:20Z
dc.date.available2014-03-18T18:02:20Z
dc.date.issued2009-08-28
dc.identifier.citationDixit, A., & Verkhivker, G. M. (2009). Hierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations. PLoS Comput Biol, 5(8). http://dx.doi.org/10.1371/journal.pcbi.1000487
dc.identifier.urihttp://hdl.handle.net/1808/13231
dc.description.abstractStructural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type) and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition and the enhanced stabilization of the active kinase form. The results of this study reconcile current experimental data with insights from theoretical approaches, pointing to general mechanistic aspects of activating transitions in protein kinases.
dc.description.sponsorshipThis work was supported by The University of Kansas start-up funding.
dc.publisherPublic Library of Science
dc.rights©2009 Dixit, Verkhivker. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/
dc.subjectBiochemical simulation
dc.subjectCarcinogensis
dc.subjectCrystal structure
dc.subjectFree energy
dc.subjectKinase inhibitors
dc.subjectMutation
dc.subjectRocky mountain spotted fever
dc.subjectThermodynamics
dc.titleHierarchical Modeling of Activation Mechanisms in the ABL and EGFR Kinase Domains: Thermodynamic and Mechanistic Catalysts of Kinase Activation by Cancer Mutations
dc.typeArticle
kusw.kuauthorDixit, Anshuman
kusw.kudepartmentDepartment of Pharmaceutical Chemistry
kusw.oastatusfullparticipation
dc.identifier.doi10.1371/journal.pcbi.1000487
kusw.oaversionScholarly/refereed, publisher version
kusw.oapolicyThis item meets KU Open Access policy criteria.
dc.rights.accessrightsopenAccess


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record

©2009 Dixit, Verkhivker. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Except where otherwise noted, this item's license is described as: ©2009 Dixit, Verkhivker. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.