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- PDB-6ckx: Structure of CDK12/CycK in complex with a small molecule inhibito... -

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Basic information

Entry
Database: PDB / ID: 6ckx
TitleStructure of CDK12/CycK in complex with a small molecule inhibitor N-(4-(1-methyl-1H-pyrazol-4-yl)phenyl)-N-((1r,4r)-4-(quinazolin-2-ylamino)cyclohexyl)acetamide
Components
  • Cyclin-K
  • Cyclin-dependent kinase 12
KeywordsTRANSFERASE/INHIBITOR / Kinase / Transferase / Inhibitor / Transferase-Cell Cycle-Inhibitor complex / TRANSFERASE-INHIBITOR complex
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 / RNA polymerase II transcribes snRNA genes / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / 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-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like ...Cyclin-T2-like, C-terminal domain / Haspin like kinase domain / Cyclin, C-terminal domain / Cyclin_C / Cyclin/Cyclin-like subunit Ssn8 / Cyclin-like / Cyclin A; domain 1 / Cyclin, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / 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 / 2-Layer Sandwich / Orthogonal Bundle / Mainly Alpha / Alpha Beta
Similarity search - Domain/homology
Chem-8M1 / Cyclin-K / Cyclin-dependent kinase 12
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.8 Å
AuthorsKlein, M.G.
CitationJournal: J. Med. Chem. / Year: 2018
Title: Discovery of 3-Benzyl-1-( trans-4-((5-cyanopyridin-2-yl)amino)cyclohexyl)-1-arylurea Derivatives as Novel and Selective Cyclin-Dependent Kinase 12 (CDK12) Inhibitors.
Authors: Ito, M. / Tanaka, T. / Toita, A. / Uchiyama, N. / Kokubo, H. / Morishita, N. / Klein, M.G. / Zou, H. / Murakami, M. / Kondo, M. / Sameshima, T. / Araki, S. / Endo, S. / Kawamoto, T. / Morin, ...Authors: Ito, M. / Tanaka, T. / Toita, A. / Uchiyama, N. / Kokubo, H. / Morishita, N. / Klein, M.G. / Zou, H. / Murakami, M. / Kondo, M. / Sameshima, T. / Araki, S. / Endo, S. / Kawamoto, T. / Morin, G.B. / Aparicio, S.A. / Nakanishi, A. / Maezaki, H. / Imaeda, Y.
History
DepositionMar 1, 2018Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 26, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)145,3429
Polymers144,3884
Non-polymers9545
Water68538
1
A: Cyclin-dependent kinase 12
B: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6835
Polymers72,1942
Non-polymers4893
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1810 Å2
ΔGint-17 kcal/mol
Surface area24740 Å2
MethodPISA
2
C: Cyclin-dependent kinase 12
D: Cyclin-K
hetero molecules


Theoretical massNumber of molelcules
Total (without water)72,6594
Polymers72,1942
Non-polymers4652
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1730 Å2
ΔGint-12 kcal/mol
Surface area24830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)96.596, 107.530, 138.324
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1010A722 - 1024
2010C722 - 1024
1020B22 - 259
2020D22 - 259

NCS ensembles :
ID
1
2

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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 / Fragment: UNP RESIDUES 713-1062
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK12, CRK7, CRKRS, KIAA0904 / Production host: unidentified baculovirus
References: UniProt: Q9NYV4, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-K


Mass: 31429.172 Da / Num. of mol.: 2 / Fragment: UNP RESIDUES 1-267
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNK, CPR4 / Production host: unidentified baculovirus / References: UniProt: O75909
#3: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Mg
#4: Chemical ChemComp-8M1 / N-[4-(1-methyl-1H-pyrazol-4-yl)phenyl]-N-{trans-4-[(quinazolin-2-yl)amino]cyclohexyl}acetamide


Mass: 440.540 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H28N6O
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 38 / Source method: isolated from a natural source / Formula: H2O

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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: 2.49 Å3/Da / Density % sol: 50.56 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop
Details: 0.1 M HEPES (PH 6.5), 18% PEG 3350, 0.2 M MGCL2, AND 1 MM SARCOSINE, VAPOR DIFFUSION, HANGING DROP, TEMPERATURE 297K

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Data collection

DiffractionMean temperature: 173 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.3 / Wavelength: 0.98 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 15, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.75→50 Å / Num. obs: 38257 / % possible obs: 99.9 % / Redundancy: 6.9 % / Net I/σ(I): 13.9
Reflection shellResolution: 2.75→2.8 Å

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Processing

Software
NameVersionClassification
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
REFMAC5.7.0025refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.8→45.64 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.933 / SU B: 32.146 / SU ML: 0.279 / Cross valid method: THROUGHOUT / ESU R Free: 0.361 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.251 1813 5 %RANDOM
Rwork0.208 ---
obs0.21 34375 99.9 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 85.84 Å2
Baniso -1Baniso -2Baniso -3
1--1.84 Å20 Å20 Å2
2--4.36 Å20 Å2
3----2.52 Å2
Refinement stepCycle: LAST / Resolution: 2.8→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8613 0 69 38 8720
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0198895
X-RAY DIFFRACTIONr_bond_other_d0.0030.028408
X-RAY DIFFRACTIONr_angle_refined_deg1.3741.97412046
X-RAY DIFFRACTIONr_angle_other_deg0.925319331
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.03351056
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.90323.768414
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.073151549
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.5641555
X-RAY DIFFRACTIONr_chiral_restr0.0750.21313
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0219893
X-RAY DIFFRACTIONr_gen_planes_other0.0030.022070
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined
X-RAY DIFFRACTIONr_long_range_B_other
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
Refine LS restraints NCS

Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Weight position: 0.05

Ens-IDDom-IDAuth asym-IDNumberRms dev position (Å)
11A180980.08
12C180980.08
21B149230.06
22D149230.06
LS refinement shellResolution: 2.8→2.87 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.361 137 -
Rwork0.318 2506 -
obs--99.96 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.80220.052-2.97171.2944-0.88237.1510.055-0.1630.1744-0.00850.14860.0417-0.0609-0.801-0.20360.1062-0.0151-0.0340.2926-0.01140.21322.6083-18.229533.5559
23.67011.1141-1.83113.3435-0.85743.77380.3333-0.21570.4860.156-0.0863-0.2476-0.5597-0.2252-0.2470.11320.03130.04340.0537-0.02340.146541.8432-16.174666.9862
33.23670.0152-1.57161.55560.10286.68610.05730.33890.2946-0.11920.0173-0.1227-0.31970.7989-0.07460.1441-0.0494-0.04640.19370.03420.2191-22.9989-14.464135.6695
45.1136-2.7595-0.30165.55990.18833.23380.10410.3137-0.1587-0.1073-0.06960.3635-0.09790.3699-0.03440.0973-0.050.03510.0898-0.03130.0731-42.627-15.17772.0833
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A722 - 1024
2X-RAY DIFFRACTION1A1101 - 1102
3X-RAY DIFFRACTION2B22 - 259
4X-RAY DIFFRACTION3C722 - 1024
5X-RAY DIFFRACTION3C1101 - 1102
6X-RAY DIFFRACTION4D22 - 259

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