Article abstract
Nature Structural & Molecular Biology 15, 1109 - 1118 (2008)
Published online: 14 September 2008 | doi:10.1038/nsmb.1486
Activation of tyrosine kinases by mutation of the gatekeeper threonine
Mohammad Azam1,2,3, Markus A Seeliger4, Nathanael S Gray2,3,5, John Kuriyan4 & George Q Daley1,2,5,6,7
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-
and -
, 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.
- Karp research building, 7th floor, Division of Pediatric Hematology/Oncology, Children's Hospital of Boston, Massachusetts 02115, USA.
- Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
- Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.
- 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.
- Department of Biological Chemistry and Molecular Pharmacology, Seeley G. Mudd building, 628A 250 Longwood Avenue, Boston, Massachusetts 02115, USA.
- Division of Hematology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
- Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
Correspondence to: George Q Daley1,2,5,6,7 e-mail: george.daley@childrens.harvard.edu
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