2. Academic Validation
  3. High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design

High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design

  • Nat Commun. 2024 Mar 13;15(1):2265. doi: 10.1038/s41467-024-46375-9.
Victoria I Cushing 1,  Adrian F Koh 2,  Junjie Feng 1,  Kaste Jurgaityte 3,  Alexander Bondke 4,  Sebastian H B Kroll 4,  Marion Barbazanges 4 5,  Bodo Scheiper 4,  Ash K Bahl 6,  Anthony G M Barrett 4,  Simak Ali 7,  Abhay Kotecha 8,  Basil J Greber 9
Affiliations

Affiliations

  • 1 The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK.
  • 2 Materials and Structural Analysis Division, Thermo Fisher Scientific, Achtseweg Noord 5, 5651, Eindhoven, The Netherlands.
  • 3 Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK.
  • 4 Department of Chemistry, Imperial College London, London, UK.
  • 5 Institut Parisien de Chimie Moléculaire, Sorbonne Université, CNRS, 4 Place Jussieu, 75252, Paris Cedex 05, France.
  • 6 Carrick Therapeutics, Nova UCD, Bellfield Innovation Park, Dublin 4, Ireland.
  • 7 Division of Cancer, Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital Campus, London, UK. [email protected].
  • 8 Materials and Structural Analysis Division, Thermo Fisher Scientific, Achtseweg Noord 5, 5651, Eindhoven, The Netherlands. [email protected].
  • 9 The Institute of Cancer Research, Chester Beatty Laboratories, 237 Fulham Road, London, SW3 6JB, UK. [email protected].
PMID: 38480681 DOI: 10.1038/s41467-024-46375-9
Abstract

Rational design of next-generation therapeutics can be facilitated by high-resolution structures of drug targets bound to small-molecule inhibitors. However, application of structure-based methods to macromolecules refractory to crystallization has been hampered by the often-limiting resolution and throughput of cryogenic electron microscopy (cryo-EM). Here, we use high-resolution cryo-EM to determine structures of the CDK-activating kinase, a master regulator of cell growth and division, in its free and nucleotide-bound states and in complex with 15 inhibitors at up to 1.8 Å resolution. Our structures provide detailed insight into inhibitor interactions and networks of water molecules in the active site of cyclin-dependent kinase 7 and provide insights into the mechanisms contributing to inhibitor selectivity, thereby providing the basis for rational design of next-generation therapeutics. These results establish a methodological framework for the use of high-resolution cryo-EM in structure-based drug design.

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