2. Academic Validation
  3. Crystal structure of the CDK11 kinase domain bound to the small-molecule inhibitor OTS964

Crystal structure of the CDK11 kinase domain bound to the small-molecule inhibitor OTS964

  • Structure. 2022 Dec 1;30(12):1615-1625.e4. doi: 10.1016/j.str.2022.10.003.
Susan Kelso 1,  Siobhan O'Brien 2,  Igor Kurinov 3,  Stephane Angers 4,  Frank Sicheri 5
Affiliations

Affiliations

  • 1 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 2 Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • 3 Department of Chemistry and Chemical Biology, Cornell University, NE-CAT, Argonne, IL 60439, USA.
  • 4 Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S 1A8, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON M5S 3M2, Canada. Electronic address: [email protected].
  • 5 Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Department of Biochemistry, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
PMID: 36327972 DOI: 10.1016/j.str.2022.10.003
Abstract

CDK11 is a cyclin-dependent kinase that controls proliferation by regulating transcription, RNA splicing, and the cell cycle. As its activity is increasingly associated with Cancer, CDK11 is an attractive target for the development of small-molecule inhibitors. However, the development of CDK11 inhibitors with limited off-target effects against Other CDKs poses a challenge based on the high conservation of sequence across family members. OTS964 is notable as it displays a measure of specificity for CDK11 in cells. To understand the basis for OTS964's specificity for CDK11, we solved a 2.6 Å crystal structure of the CDK11 kinase domain bound to OTS964. Despite the absence of cyclin, CDK11 adopts an active-like conformation when bound to OTS964. We identified Amino acids likely to contribute to the specificity of OTS964 for CDK11 and assessed their contribution to OTS964 binding by isothermal titration calorimetry (ITC) in vitro and by resistance to OTS964 in cells.

Keywords

CDK; crystal structure; inhibitor; kinase.

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