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      Survey of solution dynamics in Src kinase reveals allosteric cross talk between the ligand binding and regulatory sites

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          Abstract

          The catalytic domain of protein tyrosine kinases can interconvert between active and inactive conformations in response to regulatory inputs. We recently demonstrated that Src kinase features an allosteric network that couples substrate-binding sites. However, the extent of conformational and dynamic changes that are propagated throughout the kinase domain remains poorly understood. Here, we monitor by NMR the effect of conformationally selective inhibitors on kinase backbone dynamics. We find that inhibitor binding and activation loop autophosphorylation induces dynamic changes across the entire kinase. We identify a highly conserved amino acid, Gly449, that is necessary for Src activation. Finally, we show for the first time how the SH3–SH2 domains perturb the dynamics of the kinase domain in the context of the full length protein. We provide experimental support for long-range communication in Src kinase that leads to the relative stabilization of active or inactive conformations and modulation of substrate affinity.

          Abstract

          Src is a prototypical signaling non-receptor protein tyrosine kinase that interconverts between distinct conformations. Here the authors use variants of the kinase-inhibitor dasatinib to define three specific conformational states of the Src kinase and shed insight on the effect of conformation-specific inhibitors on Src dynamics.

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          The conformational plasticity of protein kinases.

          Protein kinases operate in a large number of distinct signaling pathways, where the tight regulation of their catalytic activity is crucial to the development and maintenance of eukaryotic organisms. The catalytic domains of different kinases adopt strikingly similar structures when they are active. By contrast, crystal structures of inactive kinases have revealed a remarkable plasticity in the kinase domain that allows the adoption of distinct conformations in response to interactions with specific regulatory domains or proteins.
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            Regulation of protein kinases; controlling activity through activation segment conformation.

            There are currently at least forty-six unique protein kinase crystal structures, twenty-four of which are available in an active state. Here we examine these structures using a structural bioinformatics approach to understand how the conformation of the activation segment controls kinase activity. Copyright 2004 Cell Press
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              Crystal structures of c-Src reveal features of its autoinhibitory mechanism.

              Src family kinases are maintained in an assembled, inactive conformation by intramolecular interactions of their SH2 and SH3 domains. Full catalytic activity requires release of these restraints as well as phosphorylation of Tyr-416 in the activation loop. In previous structures of inactive Src kinases, Tyr-416 and flanking residues are disordered. We report here four additional c-Src structures in which this segment adopts an ordered but inhibitory conformation. The ordered activation loop forms an alpha helix that stabilizes the inactive conformation of the kinase domain, blocks the peptide substrate-binding site, and prevents Tyr-416 phosphorylation. Disassembly of the regulatory domains, induced by SH2 or SH3 ligands, or by dephosphorylation of Tyr-527, could lead to exposure and phosphorylation of Tyr-416.
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                Author and article information

                Contributors
                markus.seeliger@stonybrook.edu
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                18 December 2017
                18 December 2017
                2017
                : 8
                : 2160
                Affiliations
                [1 ]ISNI 0000 0001 2216 9681, GRID grid.36425.36, Department of Pharmacological Sciences, , Stony Brook University Medical School, ; Stony Brook, NY 11794 USA
                [2 ]ISNI 0000 0001 2181 7878, GRID grid.47840.3f, QB3 Institute, , University of California, ; Berkeley, CA 94720 USA
                [3 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Structural Biophysics Laboratory, , National Cancer Institute, ; Frederick, MD 21702 USA
                [4 ]ISNI 0000 0001 2216 9681, GRID grid.36425.36, Department of Chemistry, , Stony Brook University, ; Stony Brook, NY 11790 USA
                Article
                2240
                10.1038/s41467-017-02240-6
                5735167
                36bf662b-d7eb-4e28-8bcb-e92e8840aab3
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 20 June 2017
                : 15 November 2017
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