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Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases†

  1. Douglas J. Marcotte1,
  2. Yu-Ting Liu1,
  3. Robert M. Arduini1,
  4. Catherine A. Hession1,
  5. Konrad Miatkowski1,
  6. Craig P. Wildes1,
  7. Patrick F. Cullen1,
  8. Victor Hong1,
  9. Brian T. Hopkins1,
  10. Elisabeth Mertsching2,
  11. Tracy J. Jenkins1,
  12. Michael J. Romanowski3,‡,
  13. Darren P. Baker1,
  14. Laura F. Silvian1,*

Article first published online: 5 JAN 2010

DOI: 10.1002/pro.321

Issue

Protein Science

Protein Science

Volume 19, Issue 3, pages 429–439, March 2010

Additional Information

How to Cite

Marcotte, D. J., Liu, Y.-T., Arduini, R. M., Hession, C. A., Miatkowski, K., Wildes, C. P., Cullen, P. F., Hong, V., Hopkins, B. T., Mertsching, E., Jenkins, T. J., Romanowski, M. J., Baker, D. P. and Silvian, L. F. (2010), Structures of human Bruton's tyrosine kinase in active and inactive conformations suggest a mechanism of activation for TEC family kinases. Protein Science, 19: 429–439. doi: 10.1002/pro.321

Author Information

  1. 1

    Biogen Idec, Inc., Drug Discovery Department, 12 Cambridge Center, Cambridge, Massachusetts 02142

  2. 2

    Biogen Idec, Inc., 5200 Research Place, San Diego, California 92122

  3. 3

    Sunesis Pharmaceuticals, Inc., 395 Oyster Point Boulevard, South San Francisco, California 94080

  1. ‡

    Novartis Institutes for Biomedical Research, Cambridge, MA 02139

*Biogen Idec, Inc., 12 Cambridge Center, Cambridge, MA 02142

  1. †

    Disclosure: All authors (with the exception of M. J. Romanowski) are employees of Biogen Idec and own company stock.

Publication History

  1. Issue published online: 22 FEB 2010
  2. Article first published online: 5 JAN 2010
  3. Manuscript Accepted: 14 DEC 2009
  4. Manuscript Revised: 11 DEC 2009
  5. Manuscript Received: 12 OCT 2009

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Keywords:

  • Bruton's tyrosine kinase;
  • BTK;
  • Dasatinib;
  • Celera compound;
  • TEC-family;
  • crystal structure

Abstract

Bruton's tyrosine kinase (BTK), a member of the TEC family of kinases, plays a crucial role in B-cell maturation and mast cell activation. Although the structures of the unphosphorylated mouse BTK kinase domain and the unphosphorylated and phosphorylated kinase domains of human ITK are known, understanding the kinase selectivity profiles of BTK inhibitors has been hampered by the lack of availability of a high resolution, ligand-bound BTK structure. Here, we report the crystal structures of the human BTK kinase domain bound to either Dasatinib (BMS-354825) at 1.9 Å resolution or to 4-amino-5-(4-phenoxyphenyl)-7H-pyrrolospyrimidin- 7-yl-cyclopentane at 1.6 Å resolution. This data provides information relevant to the development of small molecule inhibitors targeting BTK and the TEC family of nonreceptor tyrosine kinases. Analysis of the structural differences between the TEC and Src families of kinases near the Trp-Glu-Ile motif in the N-terminal region of the kinase domain suggests a mechanism of regulation of the TEC family members.

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