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      Activation of tyrosine kinases by mutation of the gatekeeper threonine

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          Abstract

          Protein kinases targeted by small-molecule inhibitors develop resistance through mutation of the ‘gatekeeper’ threonine residue of the active site. Here we show that the gatekeeper mutation in the cellular forms of c-ABL, c-SRC, platelet-derived growth factor receptor-α and -β, and epidermal growth factor receptor activates the kinase and promotes malignant transformation of BaF3 cells. Structural analysis reveals that a network of hydrophobic interactions—the hydrophobic spine—characteristic of the active kinase conformation is stabilized by the gatekeeper substitution. Substitution of glycine for the residues constituting the spine disrupts the hydrophobic connectivity and inactivates the kinase. Furthermore, a small-molecule inhibitor that maximizes complementarity with the dismantled spine (compound 14) inhibits the gatekeeper mutation of BCR-ABL-T315I. These results demonstrate that mutation of the gatekeeper threonine is a common mechanism of activation for tyrosine kinases and provide structural insights to guide the development of next-generation inhibitors.

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          Most cited references 46

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          Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells.

          The bcr-abl oncogene, present in 95% of patients with chronic myelogenous leukemia (CML), has been implicated as the cause of this disease. A compound, designed to inhibit the Abl protein tyrosine kinase, was evaluated for its effects on cells containing the Bcr-Abl fusion protein. Cellular proliferation and tumor formation by Bcr-Abl-expressing cells were specifically inhibited by this compound. In colony-forming assays of peripheral blood or bone marrow from patients with CML, there was a 92-98% decrease in the number of bcr-abl colonies formed but no inhibition of normal colony formation. This compound may be useful in the treatment of bcr-abl-positive leukemias.
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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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              Targeted cancer therapy.

              Disruption of the normal regulation of cell-cycle progression and division lies at the heart of the events leading to cancer. Complex networks of regulatory factors, the tumour microenvironment and stress signals, such as those resulting from damaged DNA, dictate whether cancer cells proliferate or die. Recent progress in understanding the molecular changes that underlie cancer development offer the prospect of specifically targeting malfunctioning molecules and pathways to achieve more effective and rational cancer therapy.
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                Author and article information

                Journal
                101186374
                31761
                Nat Struct Mol Biol
                Nature structural & molecular biology
                1545-9993
                1545-9985
                8 October 2008
                14 September 2008
                October 2008
                1 April 2009
                : 15
                : 10
                : 1109-1118
                Affiliations
                [1 ]Karp research building, 7th floor, Division of Pediatric Hematology/Oncology, Children's Hospital of Boston, Massachusetts 02115, USA.
                [2 ]Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
                [3 ]Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
                [4 ]Department of Molecular and Cell Biology and Department of Chemistry, University of California, Berkeley, Howard Hughes Medical Institute, 527 Stanley Hall, MC 3220, Berkeley, California 94720-3220, USA.
                [5 ]Department of Biological Chemistry and Molecular Pharmacology, Seeley G. Mudd building, 628A 250 Longwood Avenue, Boston, Massachusetts 02115, USA.
                [6 ]Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
                [7 ]Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
                Author notes
                Correspondence should be addressed to G.Q.D. ( george.daley@ 123456childrens.harvard.edu ).

                AUTHOR CONTRIBUTIONS

                M.A. designed and performed the experiments and analyzed and interpreted the data. M.A.S. crystallized the gatekeeper mutant of the SRC kinase. N.S.G. provided the compound 14 and helped in the interpretation of the data. J.K. provided the critical input on gatekeeper mutant kinase models and supervised the solution of the SRC kinase structure. G.Q.D. supervised experimental design and data interpretation. M.A. and G.Q.D wrote the manuscript with input from M.A.S., N.S.G. and J.K. All authors approved the final manuscript.

                Article
                nihpa70040
                10.1038/nsmb.1486
                2575426
                18794843
                © 2008 Nature Publishing Group
                Funding
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: Office of the Director : NIH
                Funded by: Howard Hughes Medical Institute
                Award ID: R01 CA130876-01A1 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: Office of the Director : NIH
                Funded by: Howard Hughes Medical Institute
                Award ID: R01 CA086991-01A1 ||CA
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: Office of the Director : NIH
                Funded by: Howard Hughes Medical Institute
                Award ID: K99 GM080097-02 ||GM
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: Office of the Director : NIH
                Funded by: Howard Hughes Medical Institute
                Award ID: DP1 OD000256-01 ||OD
                Funded by: National Cancer Institute : NCI
                Funded by: National Institute of General Medical Sciences : NIGMS
                Funded by: Office of the Director : NIH
                Funded by: Howard Hughes Medical Institute
                Award ID: ||HHMI_
                Categories
                Article

                Molecular biology

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