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- PDB-7nxk: Crystal structure of human Cdk12/Cyclin K in complex with the inh... -

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Basic information

Entry
Database: PDB / ID: 7nxk
TitleCrystal structure of human Cdk12/Cyclin K in complex with the inhibitor BSJ-01-175
Components
  • Cyclin-K
  • Cyclin-dependent kinase 12
KeywordsTRANSCRIPTION / CDK12 / Cyclin K / CCNK / BSJ-01-175 / kinase
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 / cyclin binding / RNA polymerase II CTD heptapeptide repeat kinase activity / 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-UUB / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3 Å
AuthorsAnand, K. / Dust, S. / Kaltheuner, I.H. / Geyer, M.
Funding support Germany, 2items
OrganizationGrant numberCountry
German Research Foundation (DFG)GE 976/9-2 Germany
German Research Foundation (DFG)EXC2151-390873048 Germany
CitationJournal: Eur.J.Med.Chem. / Year: 2021
Title: Structure-activity relationship study of THZ531 derivatives enables the discovery of BSJ-01-175 as a dual CDK12/13 covalent inhibitor with efficacy in Ewing sarcoma.
Authors: Jiang, B. / Jiang, J. / Kaltheuner, I.H. / Iniguez, A.B. / Anand, K. / Ferguson, F.M. / Ficarro, S.B. / Seong, B.K.A. / Greifenberg, A.K. / Dust, S. / Kwiatkowski, N.P. / Marto, J.A. / ...Authors: Jiang, B. / Jiang, J. / Kaltheuner, I.H. / Iniguez, A.B. / Anand, K. / Ferguson, F.M. / Ficarro, S.B. / Seong, B.K.A. / Greifenberg, A.K. / Dust, S. / Kwiatkowski, N.P. / Marto, J.A. / Stegmaier, K. / Zhang, T. / Geyer, M. / Gray, N.S.
History
DepositionMar 18, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 12, 2021Provider: repository / Type: Initial release
Revision 2.0Jan 31, 2024Group: Advisory / Data collection ...Advisory / Data collection / Database references / Non-polymer description / Refinement description
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / pdbx_unobs_or_zero_occ_atoms
Item: _chem_comp.formula / _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
C: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)145,4786
Polymers144,3884
Non-polymers1,0902
Water1,04558
1
A: Cyclin-dependent kinase 12
B: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,7393
Polymers72,1942
Non-polymers5451
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
C: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,7393
Polymers72,1942
Non-polymers5451
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.210, 77.460, 91.530
Angle α, β, γ (deg.)103.61, 85.89, 102.56
Int Tables number1
Space group name H-MP1

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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.: 2
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.: 2
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-UUB / (E)-N-[4-[(1R,3R)-3-[[5-chloranyl-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]oxyphenyl]-4-(dimethylamino)but-2-enamide / (~{E})-~{N}-[4-[(1~{R},3~{R})-3-[[5-chloranyl-4-(1~{H}-indol-3-yl)pyrimidin-2-yl]amino]cyclohexyl]oxyphenyl]-4-(dimethylamino)but-2-enamide


Mass: 545.075 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H33ClN6O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 58 / 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: 2.53 Å3/Da / Density % sol: 51.42 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 0.1 M MES, pH 6.0, 30% PEGmixture (medium weight pegs), 0.3 M NDSB, 0.2 M MgCl2.

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 16, 2019
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 3→49 Å / Num. obs: 25438 / % possible obs: 97 % / Redundancy: 3.35 % / Rrim(I) all: 0.19 / Net I/σ(I): 5.4
Reflection shellResolution: 3→3.14 Å / Num. unique obs: 3186 / Rrim(I) all: 0.99

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Processing

Software
NameVersionClassification
PHENIX(1.18.2_3874: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4NST

4nst


Resolution: 3→49 Å / SU ML: 0.56 / Cross valid method: FREE R-VALUE / σ(F): 1.95 / Phase error: 34.82 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2636 1069 4.21 %
Rwork0.2204 --
obs0.2222 25397 96.89 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 3→49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8989 0 0 58 9047
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0039210
X-RAY DIFFRACTIONf_angle_d0.56612508
X-RAY DIFFRACTIONf_dihedral_angle_d12.9063314
X-RAY DIFFRACTIONf_chiral_restr0.0921376
X-RAY DIFFRACTIONf_plane_restr0.0031585
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
3-3.140.44021340.38433051X-RAY DIFFRACTION96
3.14-3.30.36081320.33673002X-RAY DIFFRACTION96
3.3-3.510.31481320.27292984X-RAY DIFFRACTION95
3.51-3.780.30011310.2462997X-RAY DIFFRACTION96
3.78-4.160.25741370.20593117X-RAY DIFFRACTION98
4.16-4.760.21631340.18883051X-RAY DIFFRACTION98
4.76-60.26881350.21413087X-RAY DIFFRACTION98
6-490.22211340.18163039X-RAY DIFFRACTION97

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