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- PDB-9jk1: Crystal structure of CDK12/Cyclin K in complex with covalent inhi... -

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Basic information

Entry
Database: PDB / ID: 9jk1
TitleCrystal structure of CDK12/Cyclin K in complex with covalent inhibitor YJZ5118
Components
  • Cyclin-K
  • Cyclin-dependent kinase 12
KeywordsTRANSFERASE / kinase / covalent inhibitor / selective
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 / 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 / regulation of MAP kinase activity / cyclin/CDK positive transcription elongation factor complex / negative regulation by host of viral genome replication / 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 / RNA polymerase II transcribes snRNA genes / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / 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 / RNA splicing / cyclin binding / positive regulation of transcription elongation by RNA polymerase II / TP53 Regulates Transcription of DNA Repair Genes / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / mRNA processing / protein autophosphorylation / transcription by RNA polymerase II / protein kinase activity / nuclear speck / cell division / protein serine kinase activity / DNA damage response / protein kinase binding / positive regulation of transcription by RNA polymerase II / nucleoplasm / ATP binding / nucleus
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 / : / 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
: / DI(HYDROXYETHYL)ETHER / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.72 Å
AuthorsHuang, W.X. / Zhang, P.J. / Yang, J.Z. / Ding, K.
Funding support China, 1items
OrganizationGrant numberCountry
National Natural Science Foundation of China (NSFC)32071446 China
CitationJournal: J.Med.Chem. / Year: 2025
Title: Discovery of YJZ5118 : A Potent and Highly Selective Irreversible CDK12/13 Inhibitor with Synergistic Effects in Combination with Akt Inhibition.
Authors: Yang, J. / Chang, Y. / Zhou, K. / Huang, W. / Tien, J.C. / Zhang, P. / Liu, W. / Zhou, L. / Zhou, Y. / Ren, X. / Mannan, R. / Mahapatra, S. / Zhang, Y. / Hamadeh, R. / Ervine, G. / Wang, Z. ...Authors: Yang, J. / Chang, Y. / Zhou, K. / Huang, W. / Tien, J.C. / Zhang, P. / Liu, W. / Zhou, L. / Zhou, Y. / Ren, X. / Mannan, R. / Mahapatra, S. / Zhang, Y. / Hamadeh, R. / Ervine, G. / Wang, Z. / Wang, G.X. / Chinnaiyan, A.M. / Ding, K.
History
DepositionSep 14, 2024Deposition site: PDBJ / Processing site: PDBC
Revision 1.0May 7, 2025Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)143,76010
Polymers142,2604
Non-polymers1,5006
Water905
1
A: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,9016
Polymers71,1302
Non-polymers7714
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Cyclin-dependent kinase 12
C: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)71,8594
Polymers71,1302
Non-polymers7292
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)50.200, 77.190, 91.460
Angle α, β, γ (deg.)75.880, 85.630, 77.920
Int Tables number1
Space group name H-MP1
Space group name HallP1
Symmetry operation#1: x,y,z
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
d_1ens_1(chain "A" and ((resid 717 and (name N or name...
d_2ens_1(chain "B" and (resid 717 through 720 or (resid 721...
d_1ens_2(chain "C" and (resid 20 through 54 or (resid 55...
d_2ens_2(chain "D" and (resid 20 through 137 or (resid 138...

NCS domain segments:
Dom-IDComponent-IDEns-IDBeg auth comp-IDBeg label comp-IDEnd auth comp-IDEnd label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
d_11ens_1SERSERASPASPAA717 - 10385 - 326
d_12ens_1CYSCYSCYSCYSAA1039327
d_21ens_1SERSERGLUGLUBC717 - 8875 - 175
d_22ens_1ARGARGASPASPBC890 - 1038178 - 326
d_23ens_1CYSCYSCYSCYSBC1039327
d_11ens_2THRTHRSERSERCD20 - 25922 - 261
d_21ens_2THRTHRSERSERDB20 - 22722 - 229
d_22ens_2ARGARGSERSERDB233 - 259235 - 261

NCS ensembles :
ID
ens_1
ens_2

NCS oper:
IDCodeMatrixVector
1given(0.520362902029, 0.641961235921, 0.563123629203), (0.641303263966, -0.729214076565, 0.238698458659), (0.563872834794, 0.236923198766, -0.791147789017)-21.2608487101, 30.3353652302, 22.1149630978
2given(0.499777354676, 0.640382253077, 0.583209366949), (0.649407049115, -0.722591195206, 0.236922875996), (0.573143158655, 0.260331585779, -0.777003465329)-21.7542439563, 30.7862908228, 21.6964777317

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Components

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Protein , 2 types, 4 molecules ABDC

#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: 39629.777 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: 31500.250 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

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Non-polymers , 5 types, 11 molecules

#3: Chemical ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-A1EB3 / N-[5-[[4-[(5-cyanopyridin-2-yl)amino]cyclohexyl]-[(phenylmethyl)carbamoyl]amino]-2-[4-(dimethylamino)piperidin-1-yl]phenyl]propanamide / YJZ5118


Mass: 622.803 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C36H46N8O2 / Feature type: SUBJECT OF INVESTIGATION
#5: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Mg
#6: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 5 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 47.92 %
Crystal growTemperature: 291 K / Method: vapor diffusion, sitting drop
Details: 0.1 M Bis-Tris, pH 5.8, 21.5% PEG 3350, 0.4 M MgCl2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRF / Beamline: BL18U1 / Wavelength: 0.97915 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97915 Å / Relative weight: 1
ReflectionResolution: 2.72→29.56 Å / Num. obs: 34082 / % possible obs: 97.5 % / Redundancy: 3.5 % / Biso Wilson estimate: 61.54 Å2 / CC1/2: 0.997 / Rmerge(I) obs: 0.071 / Net I/σ(I): 10.9
Reflection shellResolution: 2.72→2.85 Å / Rmerge(I) obs: 0.607 / Mean I/σ(I) obs: 2 / Num. unique obs: 4551 / CC1/2: 0.7

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
xia2data reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.72→29.56 Å / SU ML: 0.4335 / Cross valid method: FREE R-VALUE / σ(F): 1.98 / Phase error: 31.3361
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2665 1999 5.87 %
Rwork0.2482 32066 -
obs0.2493 34065 97.5 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 68.69 Å2
Refinement stepCycle: LAST / Resolution: 2.72→29.56 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8584 0 120 5 8709
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00368925
X-RAY DIFFRACTIONf_angle_d0.760812140
X-RAY DIFFRACTIONf_chiral_restr0.04951357
X-RAY DIFFRACTIONf_plane_restr0.00541535
X-RAY DIFFRACTIONf_dihedral_angle_d15.44163215
Refine LS restraints NCS
Ens-IDDom-IDAsym-IDAuth asym-IDRefine-IDTypeRms dev position (Å)
ens_1d_2AAX-RAY DIFFRACTIONTorsion NCS1.05745929723
ens_2d_2DCX-RAY DIFFRACTIONTorsion NCS0.6988514561
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.72-2.790.38821440.36742300X-RAY DIFFRACTION97.37
2.79-2.860.38021420.35472293X-RAY DIFFRACTION97.52
2.86-2.950.35491450.34182323X-RAY DIFFRACTION97.2
2.95-3.040.37791380.32252208X-RAY DIFFRACTION96.94
3.04-3.150.32061450.31482331X-RAY DIFFRACTION97.48
3.15-3.280.3581410.29452267X-RAY DIFFRACTION97.65
3.28-3.430.28011420.27732267X-RAY DIFFRACTION97.49
3.43-3.610.27921440.25742320X-RAY DIFFRACTION97.16
3.61-3.830.27421430.24062295X-RAY DIFFRACTION97.79
3.83-4.130.21531430.23262289X-RAY DIFFRACTION97.67
4.13-4.540.24051440.20832308X-RAY DIFFRACTION97.85
4.54-5.20.23561420.22042274X-RAY DIFFRACTION97.7
5.2-6.530.27881420.24892296X-RAY DIFFRACTION97.72
6.53-29.560.20771440.20132295X-RAY DIFFRACTION97.6

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