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- PDB-8p81: Crystal structure of human Cdk12/Cyclin K in complex with inhibit... -

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Basic information

Entry
Database: PDB / ID: 8p81
TitleCrystal structure of human Cdk12/Cyclin K in complex with inhibitor SR-4835
Components
  • Cyclin-K
  • Cyclin-dependent kinase 12
KeywordsTRANSCRIPTION / Cyclin-dependent kinase / inhibitor / SR-4835 / Cdk12 / Cyclin K
Function / homology
Function and homology information


cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / negative regulation of stem cell differentiation / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase ...cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / negative regulation of stem cell differentiation / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase / regulation of cyclin-dependent protein serine/threonine kinase activity / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RNA polymerase II transcribes snRNA genes / regulation of signal transduction / cyclin-dependent kinase / Formation of HIV elongation complex in the absence of HIV Tat / cyclin-dependent protein serine/threonine kinase activity / RNA Polymerase II Transcription Elongation / Formation of RNA Pol II elongation complex / RNA Polymerase II Pre-transcription Events / RNA polymerase II CTD heptapeptide repeat kinase activity / cyclin binding / RNA splicing / TP53 Regulates Transcription of DNA Repair Genes / positive regulation of transcription elongation by RNA polymerase II / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / mRNA processing / transcription by RNA polymerase II / protein autophosphorylation / protein kinase activity / nuclear speck / cell cycle / cell division / protein serine kinase activity / DNA damage response / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus
Similarity search - Function
Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily ...Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / 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
Similarity search - Domain/homology
Chem-RMF / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.68 Å
AuthorsAnand, K. / Schmitz, M. / Geyer, M.
Funding support Germany, 1items
OrganizationGrant numberCountry
German Research Foundation (DFG)EXC2151-390873048 Germany
CitationJournal: J.Biol.Chem. / Year: 2023
Title: The reversible inhibitor SR-4835 binds Cdk12/cyclin K in a noncanonical G-loop conformation.
Authors: Schmitz, M. / Kaltheuner, I.H. / Anand, K. / Duster, R. / Moecking, J. / Monastyrskyi, A. / Duckett, D.R. / Roush, W.R. / Geyer, M.
History
DepositionMay 31, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 22, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 13, 2023Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Dec 27, 2023Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cyclin-dependent kinase 12
B: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6943
Polymers72,1942
Non-polymers4991
Water43224
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2560 Å2
ΔGint-8 kcal/mol
Surface area24990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.042, 137.906, 58.471
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#1: Protein Cyclin-dependent kinase 12 / Cdc2-related kinase / arginine/serine-rich / CrkRS / Cell division cycle 2-related protein kinase 7 ...Cdc2-related kinase / arginine/serine-rich / CrkRS / Cell division cycle 2-related protein kinase 7 / CDC2-related protein kinase 7 / Cell division protein kinase 12 / hCDK12


Mass: 40764.992 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK12, CRK7, CRKRS, KIAA0904 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q9NYV4, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-K


Mass: 31429.172 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNK, CPR4 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O75909
#3: Chemical ChemComp-RMF / ~{N}-[[5,6-bis(chloranyl)-1~{H}-benzimidazol-2-yl]methyl]-9-(1-methylpyrazol-4-yl)-2-morpholin-4-yl-purin-6-amine


Mass: 499.356 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: C21H20Cl2N10O / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 24 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

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Sample preparation

CrystalDensity Matthews: 2.88 Å3/Da / Density % sol: 57.3 %
Crystal growTemperature: 288 K / Method: vapor diffusion, hanging drop / pH: 6 / Details: 0.1 M MOPS pH 6.5, 30% PEG mix, 0.1 M NDSB

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 25, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 2.68→57.31 Å / Num. obs: 21122 / % possible obs: 96.3 % / Redundancy: 12.8 % / CC1/2: 1 / Net I/σ(I): 12.4
Reflection shellResolution: 2.68→2.77 Å / Num. unique obs: 1520 / CC1/2: 0.464

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Processing

Software
NameVersionClassification
PHENIX(1.20.1_4487: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.68→57.31 Å / SU ML: 0.33 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.91 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2548 1209 10 %
Rwork0.207 --
obs0.2116 12086 50.27 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.68→57.31 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4504 0 34 24 4562
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.002
X-RAY DIFFRACTIONf_angle_d0.433
X-RAY DIFFRACTIONf_dihedral_angle_d11.8311716
X-RAY DIFFRACTIONf_chiral_restr0.037686
X-RAY DIFFRACTIONf_plane_restr0.003805
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.68-2.790.5384150.4264138X-RAY DIFFRACTION6
2.79-2.920.4628330.4206302X-RAY DIFFRACTION13
2.92-3.070.4373470.366418X-RAY DIFFRACTION18
3.07-3.260.343660.3405600X-RAY DIFFRACTION25
3.26-3.520.393540.3175479X-RAY DIFFRACTION20
3.52-3.870.28941740.25271563X-RAY DIFFRACTION65
3.87-4.430.24132660.19942390X-RAY DIFFRACTION99
4.43-5.580.23512690.1922427X-RAY DIFFRACTION100
5.58-57.310.24742850.19062560X-RAY DIFFRACTION100
Refinement TLS params.Method: refined / Origin x: 34.0111 Å / Origin y: 23.812 Å / Origin z: 21.5025 Å
111213212223313233
T0.4311 Å20.067 Å20.0171 Å2-0.3894 Å20.0346 Å2--0.2698 Å2
L4.0003 °20.6045 °2-0.1446 °2-1.0325 °20.2544 °2--0.7508 °2
S0.0896 Å °0.5022 Å °-0.1939 Å °-0.0754 Å °-0.0442 Å °-0.1335 Å °0.1688 Å °-0.0068 Å °-0.0309 Å °
Refinement TLS groupSelection details: all

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