title: Activation pathway of Src kinase reveals intermediate states as targets for drug design.
abstract: Unregulated activation of Src kinases leads to aberrant signalling, uncontrolled growth and differentiation of cancerous cells. Reaching a complete mechanistic understanding of large-scale conformational transformations underlying the activation of kinases could greatly help in the development of therapeutic drugs for the treatment of these pathologies. In principle, the nature of conformational transition could be modelled in silico via atomistic molecular dynamics simulations, although this is very challenging because of the long activation timescales. Here we employ a computational paradigm that couples transition pathway techniques and Markov state model-based massively distributed simulations for mapping the conformational landscape of c-src tyrosine kinase. The computations provide the thermodynamics and kinetics of kinase activation for the first time, and help identify key structural intermediates. Furthermore, the presence of a novel allosteric site in an intermediate state of c-src that could be potentially used for drug design is predicted.
authors.affiliation: 1] Department of Chemistry, Stanford University, Stanford, California 94305, USA [2] SIMBIOS NIH Center for biomedical computation, Stanford University, Stanford, California 94305, USA.
authors.forename: Diwakar
authors.initials: D
authors.lastname: Shukla
authors.affiliation: Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Yilin
authors.initials: Y
authors.lastname: Meng
authors.affiliation: 1] Department of Biochemistry and Molecular Biology, Gordon Center for Integrative Science, The University of Chicago, Chicago, Illinois 60637, USA [2] Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439, USA.
authors.forename: Benoît
authors.initials: B
authors.lastname: Roux
authors.affiliation: 1] Department of Chemistry, Stanford University, Stanford, California 94305, USA [2] SIMBIOS NIH Center for biomedical computation, Stanford University, Stanford, California 94305, USA.
authors.forename: Vijay S
authors.initials: VS
authors.lastname: Pande
mesh_terms: D000495:Allosteric Site; D019295:Computational Biology; D015195:Drug Design; D006801:Humans; D056004:Molecular Dynamics Simulation; D013816:Thermodynamics; D019061:src-Family Kinases / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D019061:src-Family Kinases