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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Author and article information

Journal

Journal ID (nlm-journal-id): 101186374

Journal ID (pubmed-jr-id): 31761

Journal ID (nlm-ta): Nat Struct Mol Biol

Title: Nature structural & molecular biology

ISSN (Print): 1545-9993

ISSN (Electronic): 1545-9985

Publication date Nihms-submitted: 8 October 2008

Publication date (Electronic): 14 September 2008

Publication date (Print): October 2008

Publication date PMC-release: 1 April 2009

Volume: 15

Issue: 10

Pages: 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

Manuscript ID: nihpa70040

DOI: 10.1038/nsmb.1486

PMC ID: 2575426

PubMed ID: 18794843

SO-VID: 49c1c38d-2f1c-47c6-89ca-b737bf83c82b

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