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2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942.

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Greber BJ, Remis J, Ali S, Nogales E
OpenAccess logo Biophys J 120 677-686 (2021)
Cited: 12 times
EuropePMC logo PMID: 33476598

Abstract

The human CDK-activating kinase (CAK), composed of CDK7, cyclin H, and MAT1, is involved in the control of transcription initiation and the cell cycle. Because of these activities, it has been identified as a promising target for cancer chemotherapy. A number of CDK7 inhibitors have entered clinical trials, among them ICEC0942 (also known as CT7001). Structural information can aid in improving the affinity and specificity of such drugs or drug candidates, reducing side effects in patients. Here, we have determined the structure of the human CAK in complex with ICEC0942 at 2.5 Å-resolution using cryogenic electron microscopy. Our structure reveals conformational differences of ICEC0942 compared with previous X-ray crystal structures of the CDK2-bound complex, and highlights the critical ability of cryogenic electron microscopy to resolve structures of drug-bound protein complexes without the need to crystalize the protein target.

Articles - 7b5q mentioned but not cited (1)

  1. 2.5 Å-resolution structure of human CDK-activating kinase bound to the clinical inhibitor ICEC0942. Greber BJ, Remis J, Ali S, Nogales E. Biophys J 120 677-686 (2021)


Reviews citing this publication (2)

  1. Biophysical and Integrative Characterization of Protein Intrinsic Disorder as a Prime Target for Drug Discovery. Luo S, Wohl S, Zheng W, Yang S. Biomolecules 13 530 (2023)
  2. Unveiling the noncanonical activation mechanism of CDKs: insights from recent structural studies. Li T, Tang HC, Tsai KL. Front Mol Biosci 10 1290631 (2023)

Articles citing this publication (9)

  1. Cytomegalovirus cyclin-dependent kinase ortholog vCDK/pUL97 undergoes regulatory interaction with human cyclin H and CDK7 to codetermine viral replication efficiency. Schütz M, Wangen C, Sommerer M, Kögler M, Eickhoff J, Degenhart C, Klebl B, Naing Z, Egilmezer E, Hamilton ST, Rawlinson WD, Sticht H, Marschall M. Virus Res 335 199200 (2023)
  2. Insights into the bilayer-mediated toppling mechanism of a folate-specific ECF transporter by cryo-EM. Thangaratnarajah C, Rheinberger J, Paulino C, Slotboom DJ. Proc Natl Acad Sci U S A 118 e2105014118 (2021)
  3. Emerging approaches to CDK inhibitor development, a structural perspective. Hope I, Endicott JA, Watt JE. RSC Chem Biol 4 146-164 (2023)
  4. High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design. Cushing VI, Koh AF, Feng J, Jurgaityte K, Bondke A, Kroll SHB, Barbazanges M, Scheiper B, Bahl AK, Barrett AGM, Ali S, Kotecha A, Greber BJ. Nat Commun 15 2265 (2024)
  5. Improved mammalian retromer cryo-EM structures reveal a new assembly interface. Kendall AK, Chandra M, Xie B, Wan W, Jackson LP. J Biol Chem 298 102523 (2022)
  6. Cryo-EM catalyzes the exploration of drug selectivity: The CDK7 inhibitor example. Samsó M. Biophys J 120 1304-1305 (2021)
  7. CryoEM analysis of small plant biocatalysts at sub-2 Å resolution. Dimos N, Helmer CPO, Chánique AM, Wahl MC, Kourist R, Hilal T, Loll B. Acta Crystallogr D Struct Biol 78 113-123 (2022)
  8. Discovery of Pongol, the Furanoflavonoid, as an Inhibitor of CDK7/Cyclin H/MAT1 and Its Preliminary Structure-Activity Relationship. Bhurta D, Bharate SB. ACS Omega 8 1291-1300 (2023)
  9. Dynamic inter-domain transformations mediate the allosteric regulation of human 5, 10-methylenetetrahydrofolate reductase. Blomgren LKM, Huber M, Mackinnon SR, Bürer C, Baslé A, Yue WW, Froese DS, McCorvie TJ. Nat Commun 15 3248 (2024)


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