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- PDB-6z45: CDK9-Cyclin-T1 complex bound by compound 24 -

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Basic information

Entry
Database: PDB / ID: 6z45
TitleCDK9-Cyclin-T1 complex bound by compound 24
Components
  • Cyclin-T1
  • Cyclin-dependent kinase 9
KeywordsTRANSFERASE / Inhibitor / complex / kinase
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 muscle cell differentiation / regulation of mRNA 3'-end processing / positive regulation of protein localization to chromatin / RNA polymerase II CTD heptapeptide repeat Y1 kinase activity / RNA polymerase II CTD heptapeptide repeat S2 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 muscle cell differentiation / regulation of mRNA 3'-end processing / positive regulation of protein localization to chromatin / 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 / transcription elongation factor activity / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation by host of viral transcription / positive regulation of DNA-templated transcription, elongation / RNA polymerase binding / [RNA-polymerase]-subunit kinase / negative regulation of protein localization to chromatin / regulation of cyclin-dependent protein serine/threonine kinase activity / 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 / Tat-mediated elongation of the HIV-1 transcript / cyclin-dependent protein serine/threonine kinase activity / Formation of HIV-1 elongation complex containing HIV-1 Tat / Formation of HIV elongation complex in the absence of HIV Tat / regulation of DNA repair / 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 / positive regulation of transcription elongation by RNA polymerase II / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / transcription elongation by RNA polymerase II / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / molecular condensate scaffold activity / transcription coactivator binding / PML body / cytoplasmic ribonucleoprotein granule / kinase activity / DNA-binding transcription factor binding / Estrogen-dependent gene expression / transcription by RNA polymerase II / cell population proliferation / protein kinase activity / transcription cis-regulatory region binding / regulation of cell cycle / protein phosphorylation / 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-Q6E / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.37 Å
AuthorsFerguson, A. / Collie, G.W.
CitationJournal: J.Med.Chem. / Year: 2020
Title: Discovery of AZD4573, a Potent and Selective Inhibitor of CDK9 That Enables Short Duration of Target Engagement for the Treatment of Hematological Malignancies.
Authors: Barlaam, B. / Casella, R. / Cidado, J. / Cook, C. / De Savi, C. / Dishington, A. / Donald, C.S. / Drew, L. / Ferguson, A.D. / Ferguson, D. / Glossop, S. / Grebe, T. / Gu, C. / Hande, S. / ...Authors: Barlaam, B. / Casella, R. / Cidado, J. / Cook, C. / De Savi, C. / Dishington, A. / Donald, C.S. / Drew, L. / Ferguson, A.D. / Ferguson, D. / Glossop, S. / Grebe, T. / Gu, C. / Hande, S. / Hawkins, J. / Hird, A.W. / Holmes, J. / Horstick, J. / Jiang, Y. / Lamb, M.L. / McGuire, T.M. / Moore, J.E. / O'Connell, N. / Pike, A. / Pike, K.G. / Proia, T. / Roberts, B. / San Martin, M. / Sarkar, U. / Shao, W. / Stead, D. / Sumner, N. / Thakur, K. / Vasbinder, M.M. / Varnes, J.G. / Wang, J. / Wang, L. / Wu, D. / Wu, L. / Yang, B. / Yao, T.
History
DepositionMay 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 23, 2020Provider: repository / Type: Initial release
Revision 1.1Jan 6, 2021Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2May 1, 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 1.3Nov 20, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)68,5975
Polymers67,9502
Non-polymers6473
Water00
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2150 Å2
ΔGint-15 kcal/mol
Surface area27770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)171.760, 171.760, 97.790
Angle α, β, γ (deg.)90.000, 90.000, 120.000
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: 38043.020 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: 29907.156 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-Q6E / (1~{S},3~{R})-3-acetamido-~{N}-[5-chloranyl-4-(5,5-dimethyl-4,6-dihydropyrrolo[1,2-b]pyrazol-3-yl)pyridin-2-yl]cyclohexane-1-carboxamide


Mass: 429.943 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H28ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical ChemComp-TRS / 2-AMINO-2-HYDROXYMETHYL-PROPANE-1,3-DIOL / TRIS BUFFER


Mass: 122.143 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H12NO3 / Comment: pH buffer*YM
#5: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
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: 4.08 Å3/Da / Density % sol: 69.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion
Details: 14% PEG1000, 100 mM sodium potassium phosphate, pH 6.2, 500 mM NaCl, 4 mM TCEP

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 17-ID / Wavelength: 1.00001 Å
DetectorType: DECTRIS PILATUS3 2M / Detector: PIXEL / Date: Oct 19, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00001 Å / Relative weight: 1
ReflectionResolution: 3.37→85.88 Å / Num. obs: 15063 / % possible obs: 99.5 % / Redundancy: 5.8 % / Biso Wilson estimate: 130.31 Å2 / CC1/2: 0.999 / Net I/σ(I): 16.6
Reflection shellResolution: 3.37→3.56 Å / Redundancy: 6.1 % / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2199 / CC1/2: 0.849 / % possible all: 100

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Processing

Software
NameVersionClassification
BUSTER2.11.6refinement
PDB_EXTRACT3.25data extraction
Aimlessdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: internal

Resolution: 3.37→85.88 Å / Cor.coef. Fo:Fc: 0.9554 / Cor.coef. Fo:Fc free: 0.9388 / Cross valid method: THROUGHOUT / σ(F): 0 / SU Rfree Blow DPI: 0.334
RfactorNum. reflection% reflectionSelection details
Rfree0.1882 591 3.92 %RANDOM
Rwork0.1735 ---
obs0.1741 15062 99.22 %-
Displacement parametersBiso max: 263.29 Å2 / Biso mean: 160.36 Å2 / Biso min: 104.66 Å2
Baniso -1Baniso -2Baniso -3
1-15.8868 Å20 Å20 Å2
2--15.8868 Å20 Å2
3----31.7737 Å2
Refine analyzeLuzzati coordinate error obs: 0.373 Å
Refinement stepCycle: final / Resolution: 3.37→85.88 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4603 0 43 0 4646
Biso mean--148.44 --
Num. residues----566
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1679SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes121HARMONIC2
X-RAY DIFFRACTIONt_gen_planes681HARMONIC5
X-RAY DIFFRACTIONt_it4751HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion605SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5425SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4751HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6447HARMONIC21.09
X-RAY DIFFRACTIONt_omega_torsion3.06
X-RAY DIFFRACTIONt_other_torsion19.86
LS refinement shellResolution: 3.37→3.6 Å / Rfactor Rfree error: 0 / Total num. of bins used: 8
RfactorNum. reflection% reflection
Rfree0.2452 113 4.15 %
Rwork0.2283 2608 -
all0.2291 2721 -
obs--98.69 %
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)
12.82670.401-0.35982.7602-0.95426.2681-0.3809-0.2880.47010.59010.4470.2491-0.5922-1.1512-0.0661-0.09650.2954-0.0186-0.1413-0.0751-0.139-39.5157-31.90458.4079
24.85362.3575-0.06914.14160.64322.27030.12880.266-0.67220.2629-0.1138-0.74380.1260.2757-0.0149-0.1562-0.0874-0.0535-0.28740.055-0.1337-7.7213-20.5351-10.8656
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A5 - 328
2X-RAY DIFFRACTION2{ B|* }B8 - 259

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