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- PDB-6w9e: Crystal Structure of Human CDK9/cyclinT1 in complex with MC180295 -

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Basic information

Entry
Database: PDB / ID: 6w9e
TitleCrystal Structure of Human CDK9/cyclinT1 in complex with MC180295
Components
  • Cyclin-T1
  • Cyclin-dependent kinase 9
KeywordsTRANSCRIPTION / CDK9 / CYCLIN T1 / MC180295 / complex / transcriptional regulator
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 / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / molecular condensate scaffold activity / PML body / transcription coactivator binding / cytoplasmic ribonucleoprotein granule / kinase activity / DNA-binding transcription factor binding / Estrogen-dependent gene expression / 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, N-terminal / Cyclin, N-terminal domain / Cyclin-like / domain present in cyclins, TFIIB and Retinoblastoma / Cyclin-like superfamily / : / Serine/threonine-protein kinase, active site ...: / Cyclin-T2-like, C-terminal domain / 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
PHOSPHATE ION / Chem-TO7 / Chem-TOJ / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.1 Å
AuthorsZhang, P. / Wu, J.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM119560 United States
American Cancer SocietyRSG-15-167-01-DMC United States
CitationJournal: To Be Published
Title: Comparative Modeling of CDK9 Inhibitors to Explore Selectivity and Structure-Activity Relationships
Authors: Kirubakaran, P. / Morton, G. / Zhang, P. / Zhang, H. / Abou-Gharbia, M. / Issa, J. / Wu, J. / Childers, W. / Karanicolas, J.
History
DepositionMar 22, 2020Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 1, 2021Provider: repository / Type: Initial release
Revision 1.1Oct 18, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
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 9
B: Cyclin-T1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)69,7367
Polymers68,2082
Non-polymers1,5295
Water50428
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1950 Å2
ΔGint-18 kcal/mol
Surface area27950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)173.340, 173.340, 97.368
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number146
Space group name H-MH3

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Components

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Protein , 2 types, 2 molecules AB

#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: 38111.090 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: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: P50750, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein Cyclin-T1 / Cyclin-T


Mass: 30096.453 Da / Num. of mol.: 1 / Mutation: Q77R, E96G, F241L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CCNT1
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: O60563

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Non-polymers , 4 types, 33 molecules

#3: Chemical ChemComp-TO7 / (4-amino-2-{[(1S,2S,4R)-bicyclo[2.2.1]heptan-2-yl]amino}-1,3-thiazol-5-yl)(2-nitrophenyl)methanone / MC180295


Mass: 358.415 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N4O3S
#4: Chemical ChemComp-TOJ / (4-amino-2-{[(1R,2R,4S)-bicyclo[2.2.1]heptan-2-yl]amino}-1,3-thiazol-5-yl)(2-nitrophenyl)methanone


Mass: 358.415 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C17H18N4O3S
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Formula: PO4
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 28 / 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: 4.13 Å3/Da / Density % sol: 70.2 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 6.2
Details: 0.1M Na/K phosphate pH6.2, 200mM NaCl, 4mM TCEP and 1~6% PEG1000

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-1 / Wavelength: 0.97935 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jul 21, 2018
RadiationMonochromator: Double crystal Si (111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97935 Å / Relative weight: 1
ReflectionResolution: 3.1→86.67 Å / Num. obs: 19797 / % possible obs: 99.6 % / Redundancy: 4.4 % / CC1/2: 0.999 / Rmerge(I) obs: 0.061 / Net I/σ(I): 14.9
Reflection shellResolution: 3.1→3.18 Å / Redundancy: 4.5 % / Rmerge(I) obs: 0.885 / Mean I/σ(I) obs: 1.2 / Num. unique obs: 1424 / CC1/2: 0.566 / % possible all: 96.6

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Processing

Software
NameVersionClassification
REFMAC5.8.0135refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
XDSdata scaling
PHASER1.13phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3blq

3blq


Resolution: 3.1→86.67 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.937 / SU B: 18.092 / SU ML: 0.298 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 7.028 / ESU R Free: 0.348 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING
RfactorNum. reflection% reflectionSelection details
Rfree0.221 1014 5.1 %RANDOM
Rwork0.172 ---
obs0.175 18780 99.6 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 107.3 Å2
Baniso -1Baniso -2Baniso -3
1--0.93 Å2-0.47 Å20 Å2
2---0.93 Å20 Å2
3---3.03 Å2
Refinement stepCycle: LAST / Resolution: 3.1→86.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4555 0 105 28 4688
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0194774
X-RAY DIFFRACTIONr_bond_other_d0.0030.024581
X-RAY DIFFRACTIONr_angle_refined_deg2.0521.996492
X-RAY DIFFRACTIONr_angle_other_deg1.087310523
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.945559
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.30123.907215
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.68615823
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.9381531
X-RAY DIFFRACTIONr_chiral_restr0.090.2724
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0215284
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021103
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
LS refinement shellResolution: 3.1→3.18 Å
RfactorNum. reflection% reflection
Rfree0.364 68 -
Rwork0.345 1349 -
obs--96.26 %

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