Structural basis for CDK7 activation by MAT1 and Cyclin H

Peissert, S.; Schlösser, Andreas; Kendel, Rafaela; Kuper, Jochen; Kisker, Caroline

doi:10.1073/pnas.2010885117

Cited by 33 publications

(30 citation statements)

References 57 publications

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“…3 d). Along with cyclin H, CDK7 and MNAT1 form the heterotrimeric CDK activating kinase (CAK) complex, which activates the cell cycle-related CDKs 1, 2, 4, and 6 through T-loop phosphorylation 25 , 47 . The CAK complex also associates with TFIIH wherein the kinase activity of CDK7 regulates various transcription-related processes including CTD phosphorylation of RNAPII and the recruitment of NELF to transcription start sites 48 .…”

Section: Resultsmentioning

confidence: 99%

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

Donovan

Galbraith

Espinosa

2022

Sci Rep

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Transcriptional addiction is recognized as a valid therapeutic target in cancer, whereby the dependency of cancer cells on oncogenic transcriptional regulators may be pharmacologically exploited. However, a comprehensive understanding of the key factors within the transcriptional machinery that might afford a useful therapeutic window remains elusive. Herein, we present a cross-omics investigation into the functional specialization of the transcriptional cyclin dependent kinases (tCDKs) through analysis of high-content genetic dependency, gene expression, patient survival, and drug response datasets. This analysis revealed specialization among tCDKs in terms of contributions to cancer cell fitness, clinical prognosis, and interaction with oncogenic signaling pathways. CDK7 and CDK9 stand out as the most relevant targets, albeit through distinct mechanisms of oncogenicity and context-dependent contributions to cancer survival and drug sensitivity. Genetic ablation of CDK9, but not CDK7, mimics the effect on cell viability the loss of key components of the transcriptional machinery. Pathway analysis of genetic co-dependency and drug sensitivity data show CDK7 and CDK9 have distinct relationships with major oncogenic signatures, including MYC and E2F targets, oxidative phosphorylation, and the unfolded protein response. Altogether, these results inform the improved design of therapeutic strategies targeting tCDKs in cancer.

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Section: Resultsmentioning

confidence: 99%

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

Donovan

Galbraith

Espinosa

2022

Sci Rep

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“…The human CAK is a representative of the class of important drug targets that are not easily crystallized, and which still constitute a challenge for cryo-EM because they are asymmetric and of relatively small size, with the CDK-cyclin module of the CAK having a molecular mass of only ∼85 kDa. Structures of human CAK and of the fungal homolog TFIIK, both with nucleotide ligands, have been determined recently at 2.8-Å resolution using cryo-EM ( 20 ) and at 2.6-Å using X-ray crystallography ( 21 ), whereas a human CAK complex modified by the covalently bound inhibitor THZ1 was resolved at only 3.3 Å ( 20 ). Using a 200-kV cryo-transmission electron microscope without an energy filter, we have now determined the structure of the human CAK-ICEC0942 complex at 2.5 Å, a resolution that allowed docking of ICEC0942 and analysis of the molecular interactions that are formed between the drug and its target.…”

Section: Introductionmentioning

confidence: 99%

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

Greber¹,

Remis²,

Ali³

et al. 2021

Biophysical Journal

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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.

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“…It should be noted here that the DFG (Asp-Phe-Gly) motif is highly conserved and follows the T-loop, which serves as an important regulator of the various kinase activities. 20 − 23 However, partial rearrangement of the T-loop can be induced by different kinase inhibitors for open and/or closed conformations. For example, pyrazolobenzothiazine can bind with the open conformation of the T-loop of FAK (PDB ID: 4I4E ( 24 )), while BI-4464 can bind with the closed conformation (PDB ID: 6I8Z ( 25 )) ( Figure S1 ).…”

Section: Introductionmentioning

confidence: 99%

“…As previously reported, conformational rearrangements of the kinase domain can take place upon inhibitor binding. − Generally, such rearrangements are based on one of the following processes: (i) movement of the P-loop (i.e., the glycine-rich loop), (ii) movement of the T-loop (namely, the activation loop or A-loop), or (iii) rotation of the α-C-helix in the N-lobe. It should be noted here that the DFG (Asp-Phe-Gly) motif is highly conserved and follows the T-loop, which serves as an important regulator of the various kinase activities. − However, partial rearrangement of the T-loop can be induced by different kinase inhibitors for open and/or closed conformations. For example, pyrazolobenzothiazine can bind with the open conformation of the T-loop of FAK (PDB ID: 4I4E ), while BI-4464 can bind with the closed conformation (PDB ID: 6I8Z ) (Figure S1).…”

Section: Introductionmentioning

confidence: 99%

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

et al. 2022

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Focal adhesion kinase (FAK) is a 125 kDa nonreceptor tyrosine kinase that plays an important role in many carcinomas. Thus, the targeting of FAK by small molecules is considered to be promising for cancer therapy. Some FAK inhibitors have been reported as potential anticancer drugs and have entered into clinical development; for example, VS-4718 is currently undergoing clinical trials. However, the lack of crystal structural data for the binding of VS-4718 with FAK has hindered the optimization of this anticancer agent. In this work, the VS-4718/FAK interaction model was obtained by molecular docking and molecular dynamics simulations. The binding free energies of VS-4718/FAK were also calculated using the molecular mechanics generalized Born surface area method. It was found that the aminopyrimidine group formed hydrogen bonds with the C502 residue of the hinge loop, while the D564 residue of the T-loop interacted with the amide group. In addition, I428, A452, V484, M499, G505, and L553 residues formed hydrophobic interactions with VS-4718. The obtained results therefore provide an improved understanding of the interaction between human FAK and VS-4718. Based on the obtained binding mechanism, 47 novel compounds were designed to target the adenosine 5′-triphosphate-binding pocket of human FAK, and ensemble docking was performed to assess the effects of these modifications on the inhibitor binding affinity. This work is also expected to provide additional insights into potential future target design strategies based on VS-4718.

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Structural basis for CDK7 activation by MAT1 and Cyclin H

Cited by 33 publications

References 57 publications

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

Multi-omics investigation reveals functional specialization of transcriptional cyclin dependent kinases in cancer biology

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

Molecular Docking, Molecular Dynamics Simulations, and Free Energy Calculation Insights into the Binding Mechanism between VS-4718 and Focal Adhesion Kinase

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