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- PDB-8k5r: CDK9/cyclin T1 in complex with KB-0742 -

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Basic information

Entry
Database: PDB / ID: 8k5r
TitleCDK9/cyclin T1 in complex with KB-0742
Components
  • Cyclin-T1
  • Cyclin-dependent kinase 9
KeywordsTRANSCRIPTION / KB-0742 / CDK9/cyclin T1 / CDK9 / cyclin T1
Function / homology
Function and homology information


P-TEFb complex / Interactions of Tat with host cellular proteins / 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 / nucleus localization / cyclin-dependent protein serine/threonine kinase activator activity / positive regulation by host of viral transcription ...P-TEFb complex / Interactions of Tat with host cellular proteins / 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 / nucleus localization / 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 / transcription elongation-coupled chromatin remodeling / regulation of cyclin-dependent protein serine/threonine kinase activity / replication fork processing / cellular response to cytokine stimulus / Pausing and recovery of Tat-mediated HIV elongation / Tat-mediated HIV elongation arrest and recovery / HIV elongation arrest and recovery / Pausing and recovery of HIV elongation / RNA polymerase II transcribes snRNA genes / Tat-mediated elongation of the HIV-1 transcript / Formation of HIV-1 elongation complex containing HIV-1 Tat / cyclin-dependent kinase / Formation of HIV elongation complex in the absence of HIV Tat / cyclin-dependent protein serine/threonine kinase activity / 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 / cyclin binding / molecular condensate scaffold activity / transcription elongation factor complex / transcription elongation by RNA polymerase II / TP53 Regulates Transcription of DNA Repair Genes / transcription initiation at RNA polymerase II promoter / positive regulation of transcription elongation by RNA polymerase II / SMAD2/SMAD3:SMAD4 heterotrimer regulates transcription / PML body / transcription coactivator binding / cytoplasmic ribonucleoprotein granule / kinase activity / DNA-binding transcription factor binding / Estrogen-dependent gene expression / cell population proliferation / transcription by RNA polymerase II / transcription cis-regulatory region binding / regulation of cell cycle / protein kinase activity / response to xenobiotic stimulus / cell cycle / RNA polymerase II cis-regulatory region sequence-specific DNA binding / cell division / protein phosphorylation / DNA repair / protein serine kinase activity / protein serine/threonine kinase activity / chromatin binding / regulation of transcription by RNA polymerase II / protein kinase binding / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / ATP binding / membrane / nucleus / cytosol
Similarity search - Function
: / Cyclin-T2-like, C-terminal domain / Haspin like kinase 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 / Haspin like kinase 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
Chem-VQE / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 3.751 Å
AuthorsZhou, M. / Li, H. / Gao, H. / Trotter, B.W. / Freeman, D.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2023
Title: Discovery of KB-0742, a Potent, Selective, Orally Bioavailable Small Molecule Inhibitor of CDK9 for MYC-Dependent Cancers.
Authors: Freeman, D.B. / Hopkins, T.D. / Mikochik, P.J. / Vacca, J.P. / Gao, H. / Naylor-Olsen, A. / Rudra, S. / Li, H. / Pop, M.S. / Villagomez, R.A. / Lee, C. / Li, H. / Zhou, M. / Saffran, D.C. / ...Authors: Freeman, D.B. / Hopkins, T.D. / Mikochik, P.J. / Vacca, J.P. / Gao, H. / Naylor-Olsen, A. / Rudra, S. / Li, H. / Pop, M.S. / Villagomez, R.A. / Lee, C. / Li, H. / Zhou, M. / Saffran, D.C. / Rioux, N. / Hood, T.R. / Day, M.A.L. / McKeown, M.R. / Lin, C.Y. / Bischofberger, N. / Trotter, B.W.
History
DepositionJul 24, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 6, 2023Provider: repository / Type: Initial release
Revision 1.1Dec 27, 2023Group: 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

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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)68,3833
Polymers68,0952
Non-polymers2871
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1850 Å2
ΔGint-12 kcal/mol
Surface area27900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)171.502, 171.502, 96.122
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


Mass: 38057.047 Da / Num. of mol.: 1 / Mutation: S7D,V8N,K44R,Y138F,K280A,D307E,N311E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: CDK9 / Production host: Spodoptera frugiperda (fall armyworm) / References: UniProt: P50750
#2: Protein Cyclin-T1


Mass: 30038.352 Da / Num. of mol.: 1 / Mutation: R26A,Q77R,E96G,K106R,F241L
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-VQE / (1S,3S)-N3-(5-pentan-3-ylpyrazolo[1,5-a]pyrimidin-7-yl)cyclopentane-1,3-diamine


Mass: 287.403 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H25N5 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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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 Å3/Da / Density % sol: 69.21 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / Details: 0.2M K3 citrate, 20% PEG3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 0.99999 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Jul 16, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.99999 Å / Relative weight: 1
ReflectionResolution: 3.75→85.751 Å / Num. obs: 10792 / % possible obs: 99.7 % / Redundancy: 4.7 % / Rmerge(I) obs: 0.062 / Net I/σ(I): 11.6
Reflection shellResolution: 3.75→4.19 Å / Rmerge(I) obs: 0.683 / Num. unique obs: 3092

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Processing

Software
NameVersionClassification
REFMAC5.8.0352refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 3.751→85.751 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.948 / WRfactor Rfree: 0.246 / WRfactor Rwork: 0.2 / SU B: 42.14 / SU ML: 0.551 / Average fsc free: 0.9538 / Average fsc work: 0.9625 / Cross valid method: FREE R-VALUE / ESU R Free: 0.625
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2455 537 4.977 %
Rwork0.2002 10252 -
all0.203 --
obs-10789 99.732 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 200.665 Å2
Baniso -1Baniso -2Baniso -3
1--2.508 Å2-1.254 Å20 Å2
2---2.508 Å2-0 Å2
3---8.135 Å2
Refinement stepCycle: LAST / Resolution: 3.751→85.751 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4537 0 21 0 4558
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0030.0124661
X-RAY DIFFRACTIONr_bond_other_d0.0040.0164330
X-RAY DIFFRACTIONr_angle_refined_deg0.8561.6516321
X-RAY DIFFRACTIONr_angle_other_deg0.31.56510092
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6125552
X-RAY DIFFRACTIONr_dihedral_angle_2_deg2.549532
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.4910831
X-RAY DIFFRACTIONr_dihedral_angle_6_deg11.49210218
X-RAY DIFFRACTIONr_chiral_restr0.0390.2711
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.025181
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02905
X-RAY DIFFRACTIONr_nbd_refined0.2340.2970
X-RAY DIFFRACTIONr_symmetry_nbd_other0.190.24150
X-RAY DIFFRACTIONr_nbtor_refined0.1760.22288
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0740.22432
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1310.2120
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0960.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.2220.213
X-RAY DIFFRACTIONr_nbd_other0.2310.226
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.0960.23
X-RAY DIFFRACTIONr_mcbond_it9.71920.5172226
X-RAY DIFFRACTIONr_mcbond_other9.71920.5172226
X-RAY DIFFRACTIONr_mcangle_it15.46530.7592772
X-RAY DIFFRACTIONr_mcangle_other15.46230.7592773
X-RAY DIFFRACTIONr_scbond_it8.46520.892435
X-RAY DIFFRACTIONr_scbond_other8.46320.8892436
X-RAY DIFFRACTIONr_scangle_it13.96331.1613549
X-RAY DIFFRACTIONr_scangle_other13.96231.163550
X-RAY DIFFRACTIONr_lrange_it19.833254.795253
X-RAY DIFFRACTIONr_lrange_other19.832254.7635254
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
3.751-3.8480.375340.3767940.3768280.9060.91000.376
3.848-3.9530.349580.3396970.347550.9290.9211000.339
3.953-4.0680.308290.2817330.2827620.9340.9481000.281
4.068-4.1930.298420.2377000.2417420.9490.9661000.237
4.193-4.330.256470.2396560.2417030.9640.9651000.239
4.33-4.4810.329260.2226670.2266930.9380.9681000.222
4.481-4.650.224290.1936430.1956720.9670.9761000.193
4.65-4.8390.231250.2015900.2026150.9680.9751000.201
4.839-5.0540.259320.2015950.2046270.9620.9741000.201
5.054-5.2990.257320.1915550.1955870.9610.981000.191
5.299-5.5850.299170.2115510.2135690.9470.97599.82430.211
5.585-5.9220.352210.2114940.2175160.9540.97699.80620.211
5.922-6.3290.266340.2154540.2184900.9710.97499.59180.215
6.329-6.8330.223200.2264460.2264670.9720.97399.78590.226
6.833-7.480.313110.1874210.1914350.9680.97899.31030.187
7.48-8.3550.204240.1543430.1573690.9760.98599.4580.154
8.355-9.6320.174170.1343290.1363500.9850.98998.85710.134
9.632-11.760.198130.1462730.1482910.9660.98898.28180.146
11.76-16.4770.217180.1521980.1582190.9760.98598.63010.152
16.477-85.7510.27180.3691120.3621270.9510.87894.48820.369

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