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- PDB-6gzh: Crystal Structure of Human CDK9/cyclinT1 with A86 -

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Basic information

Entry
Database: PDB / ID: 6gzh
TitleCrystal Structure of Human CDK9/cyclinT1 with A86
Components
  • Cyclin-T1
  • Cyclin-dependent kinase 9
KeywordsTRANSFERASE / CDK9 / kinase inhibitor / A86
Function / homology
Function and homology information


P-TEFb complex / Interactions of Tat with host cellular proteins / nucleus localization / 7SK snRNA binding / cyclin/CDK positive transcription elongation factor complex / regulation of mRNA 3'-end processing / positive regulation of protein localization to chromatin / regulation of muscle cell differentiation / transcription elongation factor activity / regulation of cyclin-dependent protein serine/threonine kinase activity ...P-TEFb complex / Interactions of Tat with host cellular proteins / nucleus localization / 7SK snRNA binding / cyclin/CDK positive transcription elongation factor complex / regulation of mRNA 3'-end processing / positive regulation of protein localization to chromatin / regulation of muscle cell differentiation / transcription elongation factor activity / regulation of cyclin-dependent protein serine/threonine kinase activity / host-mediated activation of viral transcription / cyclin-dependent protein serine/threonine kinase activator activity / RNA polymerase binding / positive regulation of DNA-templated transcription, elongation / [RNA-polymerase]-subunit kinase / negative regulation of protein localization to chromatin / transcription elongation-coupled chromatin remodeling / cellular response to cytokine stimulus / replication fork processing / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / RNA polymerase II transcribes snRNA genes / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / regulation of DNA repair / 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 / transcription elongation factor complex / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / positive regulation of transcription elongation by RNA polymerase II / molecular condensate scaffold activity / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / PML body / transcription coactivator binding / cytoplasmic ribonucleoprotein granule / kinase activity / Estrogen-dependent gene expression / DNA-binding transcription factor binding / transcription by RNA polymerase II / cell population proliferation / protein phosphorylation / protein kinase activity / transcription cis-regulatory region binding / regulation of cell cycle / RNA polymerase II cis-regulatory region sequence-specific DNA binding / response to xenobiotic stimulus / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / chromatin binding / protein kinase binding / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / ATP binding / nucleus / membrane / cytosol
Similarity search - Function
: / Cyclin-T2-like, C-terminal domain / 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 ...: / Cyclin-T2-like, C-terminal domain / 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 / : / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); 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-LCI / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.17 Å
AuthorsBen-neriah, Y. / Venkatachalam, A. / Minzel, W. / Fink, A. / Snir-Alkalay, I. / Vacca, J.
CitationJournal: Cell / Year: 2018
Title: Small Molecules Co-targeting CKI alpha and the Transcriptional Kinases CDK7/9 Control AML in Preclinical Models.
Authors: Minzel, W. / Venkatachalam, A. / Fink, A. / Hung, E. / Brachya, G. / Burstain, I. / Shaham, M. / Rivlin, A. / Omer, I. / Zinger, A. / Elias, S. / Winter, E. / Erdman, P.E. / Sullivan, R.W. / ...Authors: Minzel, W. / Venkatachalam, A. / Fink, A. / Hung, E. / Brachya, G. / Burstain, I. / Shaham, M. / Rivlin, A. / Omer, I. / Zinger, A. / Elias, S. / Winter, E. / Erdman, P.E. / Sullivan, R.W. / Fung, L. / Mercurio, F. / Li, D. / Vacca, J. / Kaushansky, N. / Shlush, L. / Oren, M. / Levine, R. / Pikarsky, E. / Snir-Alkalay, I. / Ben-Neriah, Y.
History
DepositionJul 4, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Aug 29, 2018Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2018Group: Data collection / Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Oct 3, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3Jan 17, 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 1.4Oct 23, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Cyclin-dependent kinase 9
B: Cyclin-T1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)118,8575
Polymers118,3272
Non-polymers5303
Water2,918162
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: microscopy
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2230 Å2
ΔGint-13 kcal/mol
Surface area27780 Å2
MethodPISA
Unit cell
Length a, b, c (Å)171.599, 171.599, 97.790
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

#1: Protein Cyclin-dependent kinase 9 / C-2K / Cell division cycle 2-like protein kinase 4 / Cell division protein kinase 9 / ...C-2K / Cell division cycle 2-like protein kinase 4 / Cell division protein kinase 9 / Serine/threonine-protein kinase PITALRE / Tat-associated kinase complex catalytic subunit


Mass: 37598.578 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK9, CDC2L4, TAK / Production host: Spodoptera frugiperda (fall armyworm)
References: UniProt: P50750, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-T1 / Cyclin-T


Mass: 80728.742 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNT1 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: O60563
#3: Chemical ChemComp-LCI / [4-[[4-[5-(cyclopropylmethyl)-1-methyl-pyrazol-4-yl]-5-fluoranyl-pyrimidin-2-yl]amino]cyclohexyl]azanium


Mass: 345.438 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H26FN6 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL


Mass: 92.094 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O3
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 162 / Source method: isolated from a natural source / Formula: H2O
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: 3.84 Å3/Da / Density % sol: 68 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 7.3
Details: CDK9/Cyclin T1 at a concentration of 4.5 mg/ml (20 mM Tris / HCl, 250 mM NaCl, 1 mM DTT, 1 mM EDTA, pH 7.3) was pre-incubated with 0.6 mM (5.1-fold molar excess) of A-86 (150 mM in DMSO) and ...Details: CDK9/Cyclin T1 at a concentration of 4.5 mg/ml (20 mM Tris / HCl, 250 mM NaCl, 1 mM DTT, 1 mM EDTA, pH 7.3) was pre-incubated with 0.6 mM (5.1-fold molar excess) of A-86 (150 mM in DMSO) and 4 mM TCEP for 1 h. 0.1 ul of the protein solution was then mixed 0.1 ul of reservoir solution (0.01 M Ca-Chloride, 0.1 M MES/NaOH, pH 6.50, 1.2 M Na-Acetate) and equilibrated at 4 C over 0.06 ml of reservoir solution. Crystals were obtained using microseeding. Well diffracting crystals appeared within 4 days and grew to full size over 8 days

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Data collection

DiffractionMean temperature: 100.15 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: MASSIF-1 / Wavelength: 0.966 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Mar 2, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.966 Å / Relative weight: 1
ReflectionResolution: 3.17→30 Å / Num. obs: 16344 / % possible obs: 89.7 % / Redundancy: 1.5 % / Rrim(I) all: 0.156 / Net I/σ(I): 3.6
Reflection shellResolution: 3.17→3.34 Å / Redundancy: 1.4 % / Mean I/σ(I) obs: 1.1 / Num. unique obs: 2244 / Rrim(I) all: 0.702 / % possible all: 83.7

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
SCALAdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3BLH

3blh


Resolution: 3.17→30 Å / Cor.coef. Fo:Fc: 0.956 / Cor.coef. Fo:Fc free: 0.901 / SU B: 49.844 / SU ML: 0.418 / Cross valid method: THROUGHOUT / ESU R Free: 0.481 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25677 857 5.3 %RANDOM
Rwork0.17055 ---
obs0.17497 15466 89.49 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 86.514 Å2
Baniso -1Baniso -2Baniso -3
1--0.36 Å2-0.18 Å20 Å2
2---0.36 Å2-0 Å2
3---1.18 Å2
Refinement stepCycle: 1 / Resolution: 3.17→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4590 0 12 162 4764
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0194706
X-RAY DIFFRACTIONr_bond_other_d0.0010.024438
X-RAY DIFFRACTIONr_angle_refined_deg1.1871.9616379
X-RAY DIFFRACTIONr_angle_other_deg0.8732.99110293
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.2675558
X-RAY DIFFRACTIONr_dihedral_angle_2_deg37.8923.963217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.41415839
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.3271531
X-RAY DIFFRACTIONr_chiral_restr0.0640.2716
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0215095
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02944
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_it2.0465.1992245
X-RAY DIFFRACTIONr_mcbond_other2.0445.1982244
X-RAY DIFFRACTIONr_mcangle_it3.5147.7912798
X-RAY DIFFRACTIONr_mcangle_other3.5147.7912799
X-RAY DIFFRACTIONr_scbond_it1.8655.3772461
X-RAY DIFFRACTIONr_scbond_other1.865.3782461
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other3.2527.9893579
X-RAY DIFFRACTIONr_long_range_B_refined6.63961.4345339
X-RAY DIFFRACTIONr_long_range_B_other6.56961.3595325
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 3.17→3.251 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.311 75 -
Rwork0.312 1074 -
obs--84.86 %
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)
12.76990.46931.31.87880.64614.6705-0.15520.0409-0.2444-0.32280.30330.37390.2487-0.7338-0.14810.2521-0.0621-0.04210.25380.12270.3035-39.505531.837834.7649
26.1262-0.5068-0.40384.13430.47562.02550.01270.21040.529-0.28880.1156-0.2193-0.1480.0792-0.12830.15170.03230.00220.04160.00970.0617-8.003320.304753.5792
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A8 - 325
2X-RAY DIFFRACTION2B8 - 259

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