A chemical switch for inhibitor-sensitive alleles of any protein kinase
Anthony C. Bishop,
Jeffrey A. Ubersax,
Dejah T. Petsch,
Dina P. Matheos,
Nathanael S. Gray,
Justin Blethrow,
Eiji Shimizu,
Joe Z. Tsien,
Peter G. Schultz,
Mark D. Rose,
John L. Wood,
David O. Morgan and
Kevan M. Shokat ()
Additional contact information
Anthony C. Bishop: Princeton University
Jeffrey A. Ubersax: University of California San Francisco
Dejah T. Petsch: Yale University
Dina P. Matheos: Department of Molecular Biology Princeton University
Nathanael S. Gray: Genomics Institute of the Novartis Research Foundation
Justin Blethrow: University of California San Francisco
Eiji Shimizu: Department of Molecular Biology Princeton University
Joe Z. Tsien: Department of Molecular Biology Princeton University
Peter G. Schultz: Genomics Institute of the Novartis Research Foundation
Mark D. Rose: Department of Molecular Biology Princeton University
John L. Wood: Yale University
David O. Morgan: University of California San Francisco
Kevan M. Shokat: Princeton University
Nature, 2000, vol. 407, issue 6802, 395-401
Abstract:
Abstract Protein kinases have proved to be largely resistant to the design of highly specific inhibitors, even with the aid of combinatorial chemistry1. The lack of these reagents has complicated efforts to assign specific signalling roles to individual kinases. Here we describe a chemical genetic strategy for sensitizing protein kinases to cell-permeable molecules that do not inhibit wild-type kinases2. From two inhibitor scaffolds, we have identified potent and selective inhibitors for sensitized kinases from five distinct subfamilies. Tyrosine and serine/threonine kinases are equally amenable to this approach. We have analysed a budding yeast strain carrying an inhibitor-sensitive form of the cyclin-dependent kinase Cdc28 (CDK1) in place of the wild-type protein. Specific inhibition of Cdc28 in vivo caused a pre-mitotic cell-cycle arrest that is distinct from the G1 arrest typically observed in temperature-sensitive cdc28 mutants3. The mutation that confers inhibitor-sensitivity is easily identifiable from primary sequence alignments. Thus, this approach can be used to systematically generate conditional alleles of protein kinases, allowing for rapid functional characterization of members of this important gene family.
Date: 2000
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DOI: 10.1038/35030148
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