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- PDB-7nxj: Crystal structure of human Cdk13/Cyclin K in complex with the inh... -

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Basic information

Entry
Database: PDB / ID: 7nxj
TitleCrystal structure of human Cdk13/Cyclin K in complex with the inhibitor THZ531
Components
  • Cyclin-K
  • Cyclin-dependent kinase 13
KeywordsTRANSCRIPTION / CDK13 / Cyclin K / CCNK / THZ531 / kinase
Function / homology
Function and homology information


cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / alternative mRNA splicing, via spliceosome / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity / RNA polymerase II CTD heptapeptide repeat T4 kinase activity / RNA polymerase II CTD heptapeptide repeat S5 kinase activity ...cyclin K-CDK12 complex / cyclin K-CDK13 complex / nuclear cyclin-dependent protein kinase holoenzyme complex / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / alternative mRNA splicing, via spliceosome / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 kinase activity / RNA polymerase II CTD heptapeptide repeat T4 kinase activity / RNA polymerase II CTD heptapeptide repeat S5 kinase activity / RNA polymerase II CTD heptapeptide repeat S7 kinase activity / 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 / hemopoiesis / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RNA polymerase II transcribes snRNA genes / regulation of signal transduction / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Formation of HIV elongation complex in the absence of HIV Tat / 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 / positive regulation of transcription elongation by RNA polymerase II / TP53 Regulates Transcription of DNA Repair Genes / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / ficolin-1-rich granule lumen / transcription by RNA polymerase II / protein kinase activity / nuclear speck / cell division / protein serine kinase activity / DNA damage response / Neutrophil degranulation / protein kinase binding / Golgi apparatus / positive regulation of transcription by RNA polymerase II / extracellular space / RNA binding / extracellular region / nucleoplasm / ATP binding / nucleus / cytosol
Similarity search - Function
Cyclin-T2-like, C-terminal domain / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, C-terminal domain / Cyclin_C / 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 / Cyclin/Cyclin-like subunit Ssn8 / Cyclin, C-terminal domain / Cyclin_C / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / Phosphorylase Kinase; domain 1 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-5I1 / Cyclin-K / Cyclin-dependent kinase 13
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.36 Å
AuthorsAnand, K. / Greifenberg, A.K. / 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 1.1Jan 31, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 1.2Nov 13, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Cyclin-dependent kinase 13
B: Cyclin-K
C: Cyclin-dependent kinase 13
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)145,0226
Polymers143,9024
Non-polymers1,1202
Water1,49583
1
A: Cyclin-dependent kinase 13
B: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,5113
Polymers71,9512
Non-polymers5601
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2080 Å2
ΔGint-6 kcal/mol
Surface area25920 Å2
MethodPISA
2
C: Cyclin-dependent kinase 13
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,5113
Polymers71,9512
Non-polymers5601
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2310 Å2
ΔGint-6 kcal/mol
Surface area25900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.880, 149.450, 92.010
Angle α, β, γ (deg.)90.00, 94.61, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Cyclin-dependent kinase 13 / CDC2-related protein kinase 5 / Cell division cycle 2-like protein kinase 5 / Cell division protein ...CDC2-related protein kinase 5 / Cell division cycle 2-like protein kinase 5 / Cell division protein kinase 13 / hCDK13 / Cholinesterase-related cell division controller


Mass: 40521.863 Da / Num. of mol.: 2 / Fragment: UNP residues 694-1039
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK13, CDC2L, CDC2L5, CHED, KIAA1791 / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: Q14004, 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-5I1 / N-[4-[(3R)-3-[[5-chloranyl-4-(1H-indol-3-yl)pyrimidin-2-yl]amino]piperidin-1-yl]carbonylphenyl]-4-(dimethylamino)butanamide


Mass: 560.090 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H34ClN7O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 83 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.36 Å3/Da / Density % sol: 47.83 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 6.8 / Details: 0.1 M MES (pH 6.8), 24% PEG 3350, 0.2 M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-1 / Wavelength: 0.972422 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 24, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.972422 Å / Relative weight: 1
ReflectionResolution: 2.36→45.86 Å / Num. obs: 54103 / % possible obs: 98.2 % / Redundancy: 3.4 % / Rrim(I) all: 0.06 / Net I/σ(I): 13.4
Reflection shellResolution: 2.36→2.44 Å / Num. unique obs: 5344 / Rrim(I) all: 0.77 / % possible all: 97.3

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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: 5EFQ

5efq


Resolution: 2.36→45.86 Å / SU ML: 0.36 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 29.78 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2518 1351 2.5 %
Rwork0.2121 --
obs0.2131 54078 98.15 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.36→45.86 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9284 0 0 83 9367
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0029504
X-RAY DIFFRACTIONf_angle_d0.60812885
X-RAY DIFFRACTIONf_dihedral_angle_d18.4043486
X-RAY DIFFRACTIONf_chiral_restr0.0411384
X-RAY DIFFRACTIONf_plane_restr0.0041638
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.36-2.440.34551340.31885210X-RAY DIFFRACTION98
2.44-2.540.37911350.29685295X-RAY DIFFRACTION98
2.54-2.660.31351350.28565259X-RAY DIFFRACTION98
2.66-2.80.33131320.27995183X-RAY DIFFRACTION97
2.8-2.970.33611360.26575335X-RAY DIFFRACTION99
2.97-3.20.33491360.25695286X-RAY DIFFRACTION99
3.2-3.520.24051350.23165283X-RAY DIFFRACTION98
3.53-4.030.26891350.215232X-RAY DIFFRACTION97
4.04-5.080.20721350.17065295X-RAY DIFFRACTION98
5.08-45.860.1971380.17545349X-RAY DIFFRACTION98
Refinement TLS params.Method: refined / Origin x: 28.789 Å / Origin y: 26.698 Å / Origin z: 29.554 Å
111213212223313233
T0.3674 Å2-0.0588 Å20.0492 Å2-0.431 Å2-0.0322 Å2--0.4299 Å2
L0.4146 °2-0.1636 °20.3958 °2-0.2076 °2-0.1501 °2--0.9953 °2
S-0.0094 Å °-0.0877 Å °0.0518 Å °0.0672 Å °0.0156 Å °-0.0414 Å °-0.1346 Å °-0.0785 Å °-0.0074 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )A695 - 1023
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )A2000
3X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )A2101 - 2116
4X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )C695 - 1017
5X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )C2000
6X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )C2101 - 2125
7X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )B21 - 264
8X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )B301 - 317
9X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )D301 - 325
10X-RAY DIFFRACTION1( CHAIN A AND ( RESID 695:1023 OR RESID 2000:2000 OR RESID 2101:2116 ) ) OR ( CHAIN C AND ( RESID 695:1017 OR RESID 2000:2000 OR RESID 2101:2125 ) ) OR ( CHAIN B AND ( RESID 21:264 OR RESID 301:317 ) ) OR ( CHAIN D AND ( RESID 301:325 OR RESID 21:267 ) )D21 - 267

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