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

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Basic information

Entry
Database: PDB / ID: 4bcf
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 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-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-T6Q / Cyclin-T1 / Cyclin-dependent kinase 9
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / OTHER / Resolution: 3.011 Å
AuthorsHole, A.J. / Baumli, S. / Wang, S. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Comparative Structural and Functional Studies of 4-(Thiazol- 5-Yl)-2-(Phenylamino)Pyrimidine-5-Carbonitrile Cdk9 Inhibitors Suggest the Basis for Isotype Selectivity.
Authors: Hole, A.J. / Baumli, S. / Shao, H. / Shi, S. / Pepper, C. / Fischer, P.M. / Wang, S. / Endicott, J.A. / Noble, M.E.M.
History
DepositionOct 2, 2012Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 9, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 27, 2013Group: Database references
Revision 1.2May 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 1.3May 22, 2019Group: Data collection / Refinement description / Category: refine / Item: _refine.pdbx_ls_cross_valid_method
Revision 1.4Oct 23, 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

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)68,6503
Polymers68,1882
Non-polymers4631
Water25214
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1790 Å2
ΔGint-11.4 kcal/mol
Surface area27600 Å2
MethodPISA
Unit cell
Length a, b, c (Å)172.316, 172.316, 98.820
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: 38068.105 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-T6Q / 2-[[3-(4-ethanoyl-1,4-diazepan-1-yl)phenyl]amino]-4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]pyrimidine-5-carbonitrile


Mass: 462.571 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26N8OS
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 14 / 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: 2.2 Å3/Da / Density % sol: 45 % / Description: NONE
Crystal growTemperature: 277 K / pH: 6.2
Details: CRYSTALS WERE GROWN AT 4C IN 10-16% PEG 1000, 100MM NAK-PHOSPHATE PH 6.2, 500MM NACL, 4MM TCEP. THEY WERE SUBSEQUENTLY SOAKED IN THE PRESENCE OF THE 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: 3.01→82.39 Å / Num. obs: 20836 / % possible obs: 96.2 % / Redundancy: 2.93 % / Rmerge(I) obs: 0.05 / Net I/σ(I): 11.37
Reflection shellResolution: 3.01→3.17 Å / Redundancy: 2.94 % / Rmerge(I) obs: 0.39 / Mean I/σ(I) obs: 1.97 / % possible all: 96.6

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
PHENIXphasing
RefinementMethod to determine structure: OTHER / Resolution: 3.011→82.393 Å / Cor.coef. Fo:Fc: 0.959 / Cor.coef. Fo:Fc free: 0.935 / SU B: 27.452 / SU ML: 0.233 / Cross valid method: THROUGHOUT / ESU R: 0.942 / ESU R Free: 0.336 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflection
Rfree0.2244 1053 5.16 %
Rwork0.1665 --
obs0.169 20826 96.212 %
Solvent computationIon probe radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 90.452 Å2
Baniso -1Baniso -2Baniso -3
1--1.939 Å2-1.939 Å20 Å2
2---1.939 Å20 Å2
3---6.289 Å2
Refinement stepCycle: LAST / Resolution: 3.011→82.393 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4550 0 33 14 4597
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0194689
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5561.976360
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.8895556
X-RAY DIFFRACTIONr_dihedral_angle_2_deg35.77723.963217
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.74215834
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.0611531
X-RAY DIFFRACTIONr_chiral_restr0.1050.2709
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0213503
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2520.2615
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3450.2756
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1790.244
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_it8.5056.9944689
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it11.87311.1521937
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it16.30521.966277
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it15.04467.97312348
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: 3.011→3.089 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.252 70 -
Rwork0.257 1464 -
obs--96.055 %
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)
11.20190.14590.19011.4849-0.0841.80070.20250.0017-0.3190.2258-0.24810.03990.43220.10160.04560.2185-0.0503-0.02530.13570.00050.095947.6102-17.8027-1.2148
22.3141-0.9778-0.21521.2094-0.01890.8642-0.00230.03170.24940.03940.0809-0.1235-0.01540.0049-0.07870.1046-0.0113-0.03520.1538-0.03730.056121.4433.6775-19.7841
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A6 - 326
2X-RAY DIFFRACTION2B8 - 259

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