EMDB-17536: Cryo-EM structure of CDK7 subunit of CAK in complex with inhibito...

Basic information

Entry

Database: EMDB / ID: EMD-17536

• Title: Cryo-EM structure of CDK7 subunit of CAK in complex with inhibitor LDC4297
• Map data: Post-processed sharpened cryo-EM map

Sample

• Complex: CDK-activating kinase
  • Protein or peptide: CDK-activating kinase assembly factor MAT1
  • Protein or peptide: Cyclin-dependent kinase 7
• Ligand: 2-[(3S)-piperidin-3-yl]oxy-8-propan-2-yl-N-[(2-pyrazol-1-ylphenyl)methyl]pyrazolo[1,5-a][1,3,5]triazin-4-amine
• Ligand: water

• Keywords: Kinase / Inhibitor / Transcription / Cell Cycle / TRANSFERASE

Function / homology

Function:

ventricular system development / cyclin-dependent protein kinase activating kinase holoenzyme complex / snRNA transcription by RNA polymerase II / CAK-ERCC2 complex / transcription factor TFIIK complex / adult heart development / transcription factor TFIIH core complex / cyclin-dependent protein serine/threonine kinase activator activity / transcription factor TFIIH holo complex / [RNA-polymerase]-subunit kinase / RNA Polymerase I Transcription Termination / RNA Pol II CTD phosphorylation and interaction with CE during HIV infection / RNA Pol II CTD phosphorylation and interaction with CE / Formation of the Early Elongation Complex / Formation of the HIV-1 Early Elongation Complex / mRNA Capping / HIV Transcription Initiation / RNA Polymerase II HIV Promoter Escape / Transcription of the HIV genome / RNA Polymerase II Promoter Escape / RNA Polymerase II Transcription Pre-Initiation And Promoter Opening / RNA Polymerase II Transcription Initiation / RNA Polymerase II Transcription Initiation And Promoter Clearance / regulation of G1/S transition of mitotic cell cycle / RNA Polymerase I Transcription Initiation / RNA polymerase II transcribes snRNA genes / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / ATP-dependent activity, acting on DNA / cyclin-dependent kinase / Formation of HIV elongation complex in the absence of HIV Tat / cyclin-dependent protein serine/threonine kinase activity / Cyclin E associated events during G1/S transition / RNA Polymerase II Transcription Elongation / Cyclin A/B1/B2 associated events during G2/M transition / Formation of RNA Pol II elongation complex / Cyclin A:Cdk2-associated events at S phase entry / RNA Polymerase II Pre-transcription Events / RNA polymerase II CTD heptapeptide repeat kinase activity / male germ cell nucleus / nucleotide-excision repair / RNA Polymerase I Promoter Escape / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / positive regulation of smooth muscle cell proliferation / NoRC negatively regulates rRNA expression / Transcription-Coupled Nucleotide Excision Repair (TC-NER) / Formation of TC-NER Pre-Incision Complex / fibrillar center / Formation of Incision Complex in GG-NER / response to calcium ion / Dual incision in TC-NER / G1/S transition of mitotic cell cycle / Gap-filling DNA repair synthesis and ligation in TC-NER / Cyclin D associated events in G1 / RUNX1 regulates transcription of genes involved in differentiation of HSCs / transcription by RNA polymerase II / protein stabilization / regulation of cell cycle / protein kinase activity / cell cycle / phosphorylation / cell division / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / regulation of transcription by RNA polymerase II / negative regulation of apoptotic process / perinuclear region of cytoplasm / positive regulation of transcription by RNA polymerase II / zinc ion binding / nucleoplasm / ATP binding / nucleus / plasma membrane / cytoplasm / cytosol

Domain/homology:

Cyclin-dependent kinase 7 / Cdk-activating kinase assembly factor MAT1/Tfb3 / Cdk-activating kinase assembly factor MAT1, centre / CDK-activating kinase assembly factor MAT1 / Zinc finger, C3HC4 type (RING finger) / Ubiquitin interacting motif / Ubiquitin-interacting motif (UIM) domain profile. / Zinc finger, RING-type, conserved site / Zinc finger RING-type signature. / Ring finger / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily

Component:

Cyclin-dependent kinase 7 / CDK-activating kinase assembly factor MAT1

• Biological species: Homo sapiens (human)
• Method: single particle reconstruction / cryo EM / Resolution: 2.1 Å
• Authors: Cushing VI / Koh AF / Feng J / Jurgaityte K / Bahl AK / Ali S / Kotecha A / Greber BJ

Funding support

United Kingdom, 1 items

Organization	Grant number	Country
Medical Research Council (MRC, United Kingdom)	MR/V009354/1	United Kingdom

• Citation: Journal: Nat Commun / Year: 2024; Title: High-resolution cryo-EM of the human CDK-activating kinase for structure-based drug design.; Authors: Victoria I Cushing / Adrian F Koh / Junjie Feng / Kaste Jurgaityte / Alexander Bondke / Sebastian H B Kroll / Marion Barbazanges / Bodo Scheiper / Ash K Bahl / Anthony G M Barrett / Simak Ali / Abhay Kotecha / Basil J Greber / ; 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.

History

Deposition	May 30, 2023	-
Header (metadata) release	Mar 20, 2024	-
Map release	Mar 20, 2024	-
Update	Mar 27, 2024	-
Current status	Mar 27, 2024	Processing site: PDBe / Status: Released