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- PDB-4bcg: Structure of CDK9 in complex with cyclin T and a 2-amino-4-hetero... -

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Basic information

Entry
Database: PDB / ID: 4bcg
TitleStructure of CDK9 in complex with cyclin T and a 2-amino-4-heteroaryl- pyrimidine inhibitor
Components
  • CYCLIN-DEPENDENT KINASE 9
  • CYCLIN-T1
KeywordsTRANSFERASE/CELL CYCLE / TRANSFERASE-CELL CYCLE COMPLEX / CDK-CYCLIN COMPLEX / TRANSCRIPTION-PROTEIN BINDING / STRUCTURE-BASED DRUG DESIGN
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-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-T3C / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 3.085 Å
AuthorsHole, A.J. / Baumli, S. / Wang, S. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Substituted 4-(Thiazol-5-Yl)-2-(Phenylamino)Pyrimidines are Highly Active Cdk9 Inhibitors: Synthesis, X-Ray Crystal Structure, Sar and Anti-Cancer Activities.
Authors: Shao, H. / Shi, S. / Huang, S. / Hole, A. / Abbas, A.Y. / Baumli, S. / Liu, X. / Lam, F. / Foley, D.W. / Fischer, P.M. / Noble, M. / Endicott, J.A. / Pepper, C. / Wang, S.
History
DepositionOct 2, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 17, 2013Provider: repository / Type: Initial release
Revision 1.1May 15, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Experimental preparation / Other
Category: exptl_crystal_grow / pdbx_database_proc ...exptl_crystal_grow / pdbx_database_proc / pdbx_database_status / struct_conn
Item: _exptl_crystal_grow.temp / _pdbx_database_status.recvd_author_approval / _struct_conn.pdbx_leaving_atom_flag
Revision 1.2Nov 13, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Structure summary
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_entry_details / pdbx_modification_feature / struct_conn / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr1_label_seq_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_conn.ptnr2_label_seq_id / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)68,7785
Polymers68,1742
Non-polymers6053
Water28816
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2350 Å2
ΔGint-13.5 kcal/mol
Surface area27720 Å2
MethodPISA
Unit cell
Length a, b, c (Å)172.800, 172.800, 98.880
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: 38054.082 Da / Num. of mol.: 1 / Fragment: RESIDUES 2-330
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PVL1392 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9
References: UniProt: P50750, cyclin-dependent kinase, [RNA-polymerase]-subunit kinase
#2: Protein CYCLIN-T1 / CYCT1 / CYCLIN-T


Mass: 30119.426 Da / Num. of mol.: 1 / Fragment: RESIDUES 2-259 / Mutation: YES
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Plasmid: PVL1392 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / Strain (production host): SF9 / References: UniProt: O60563
#3: Chemical ChemComp-T3C / 2-[[3-(1,4-diazepan-1-yl)phenyl]amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile


Mass: 420.534 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C21H24N8S
#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.: 16 / 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: 2.3 Å3/Da / Density % sol: 45 % / Description: NONE
Crystal growTemperature: 277 K / pH: 6.2
Details: CRYSTALS WERE GROWN AT 4C USING 10-16% PEG 1000, 100MM NAK-PHOSPHATE PH 6.2, 500MM NACL, 4MM TCEP AS THE PRECIPITANT SOLUTION. THEY WERE SUBSEQUENTLY SOAKED IN THE PRESENCE OF COMPOUND.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 3.08→86.4 Å / Num. obs: 20079 / % possible obs: 99 % / Redundancy: 3.5 % / Rmerge(I) obs: 0.06 / Net I/σ(I): 6.87
Reflection shellResolution: 3.08→3.25 Å / Redundancy: 3.4 % / Rmerge(I) obs: 0.51 / Mean I/σ(I) obs: 1.51 / % possible all: 99.6

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
PHENIXphasing
RefinementMethod to determine structure: OTHER / Resolution: 3.085→82.634 Å / Cor.coef. Fo:Fc: 0.963 / Cor.coef. Fo:Fc free: 0.947 / SU B: 27.464 / SU ML: 0.22 / Cross valid method: THROUGHOUT / ESU R: 1.636 / ESU R Free: 0.307 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflection
Rfree0.1972 1023 5.18 %
Rwork0.1611 --
obs0.163 20066 98.998 %
Solvent computationIon probe radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 90.825 Å2
Baniso -1Baniso -2Baniso -3
1--0.468 Å2-0.468 Å20 Å2
2---0.468 Å20 Å2
3---1.519 Å2
Refinement stepCycle: LAST / Resolution: 3.085→82.634 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4591 0 42 16 4649
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194738
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.4331.9726421
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3855562
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.91223.991218
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.02815848
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.7811531
X-RAY DIFFRACTIONr_chiral_restr0.1010.2716
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213529
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2620.2589
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3460.2799
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2320.228
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_it7.7336.5514738
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it12.04410.731998
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it16.28620.827280
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it13.50363.01212343
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: 3.085→3.165 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.342 80 -
Rwork0.286 1433 -
obs--99.671 %
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)
11.71950.07370.02062.2473-0.61093.10040.2372-0.0977-0.48860.2646-0.23190.00870.54690.0904-0.00530.2095-0.068-0.05870.12330.00570.162847.4486-17.8388-1.4617
23.0359-1.2695-0.42432.04470.07621.0546-0.0091-0.02380.26450.12410.0981-0.2325-0.05370.0505-0.0890.0906-0.0112-0.04390.1401-0.03430.059821.53633.6576-20.3435
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A7 - 327
2X-RAY DIFFRACTION2B8 - 259

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