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- PDB-4bcq: Structure of CDK2 in complex with cyclin A and a 2-amino-4-hetero... -

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Basic information

Entry
Database: PDB / ID: 4bcq
TitleStructure of CDK2 in complex with cyclin A and a 2-amino-4-heteroaryl- pyrimidine inhibitor
Components
  • (CYCLIN-A2) x 2
  • CYCLIN-DEPENDENT KINASE 2
KeywordsTRANSFERASE/CELL CYCLE / TRANSFERASE-CELL CYCLE COMPLEX / CDK-CYCLIN COMPLEX / CYCLIN A / CYCLIN- DEPENDENT KINASE 2 / STRUCTURE-BASED DRUG DESIGN
Function / homology
Function and homology information


cell cycle G1/S phase transition / cyclin-dependent protein serine/threonine kinase regulator activity / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity ...cell cycle G1/S phase transition / cyclin-dependent protein serine/threonine kinase regulator activity / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / Y chromosome / cyclin-dependent protein kinase activity / Phosphorylation of proteins involved in G1/S transition by active Cyclin E:Cdk2 complexes / positive regulation of heterochromatin formation / p53-Dependent G1 DNA Damage Response / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / microtubule organizing center / regulation of DNA replication / telomere maintenance in response to DNA damage / centrosome duplication / G0 and Early G1 / Telomere Extension By Telomerase / Activation of the pre-replicative complex / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Cajal body / Activation of ATR in response to replication stress / Cyclin E associated events during G1/S transition / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / regulation of G2/M transition of mitotic cell cycle / mitotic G1 DNA damage checkpoint signaling / cellular response to nitric oxide / post-translational protein modification / cyclin binding / regulation of mitotic cell cycle / positive regulation of DNA replication / meiotic cell cycle / male germ cell nucleus / G1/S transition of mitotic cell cycle / peptidyl-serine phosphorylation / DNA Damage/Telomere Stress Induced Senescence / potassium ion transport / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G2/M transition of mitotic cell cycle / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / Cyclin D associated events in G1 / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / regulation of gene expression / Senescence-Associated Secretory Phenotype (SASP) / transcription regulator complex / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / chromatin remodeling / protein domain specific binding / cell division / protein serine kinase activity / DNA repair / protein serine/threonine kinase activity / positive regulation of cell population proliferation / DNA-templated transcription / centrosome / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II / signal transduction / nucleoplasm / ATP binding / nucleus / cytoplasm / cytosol
Similarity search - Function
Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin-like / Cyclin, C-terminal domain / Cyclin_C / 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-TJF / Cyclin-dependent kinase 2 / Cyclin-A2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
BOS TAURUS (domestic cattle)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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 1.2Oct 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.pdbx_dist_value / _struct_conn.pdbx_leaving_atom_flag / _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 2
B: CYCLIN-A2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,5866
Polymers128,7154
Non-polymers8712
Water5,963331
1
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7973
Polymers64,3612
Non-polymers4361
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3060 Å2
ΔGint-12.4 kcal/mol
Surface area25590 Å2
MethodPISA
2
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7893
Polymers64,3532
Non-polymers4361
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3050 Å2
ΔGint-10.3 kcal/mol
Surface area25830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.080, 141.160, 155.520
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein CYCLIN-DEPENDENT KINASE 2 / 2.7.11.22 / CELL DIVISION PROTEIN KINASE 2 / P33 PROTEIN KINASE


Mass: 34297.715 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P24941, cyclin-dependent kinase
#2: Protein CYCLIN-A2 / CYCLIN-A


Mass: 30055.689 Da / Num. of mol.: 1 / Fragment: RESIDUES 169-429
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) BOS TAURUS (domestic cattle) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P30274
#3: Protein CYCLIN-A2 / CYCLIN-A


Mass: 30063.732 Da / Num. of mol.: 1 / Fragment: RESIDUES 169-429
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) BOS TAURUS (domestic cattle) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P30274
#4: Chemical ChemComp-TJF / 4-[4-methyl-2-(methylamino)-1,3-thiazol-5-yl]-2-{[3-(morpholin-4-ylcarbonyl)phenyl]amino}pyrimidine-5-carbonitrile


Mass: 435.502 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H21N7O2S
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 331 / 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

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Sample preparation

CrystalDensity Matthews: 3.4 Å3/Da / Density % sol: 63 % / Description: NONE
Crystal growDetails: COCRYSTALS WERE GROWN IN 1-1.25M AMMONIUM SULFATE, 0.5-0.9M KCL, 100MM HEPES, PH 7.0, 5MM DTT AND IN THE PRESENCE OF COMPOUND.

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.98
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 2.19→52.26 Å / Num. obs: 65528 / % possible obs: 97.9 % / Redundancy: 3.2 % / Biso Wilson estimate: 43.82 Å2 / Rmerge(I) obs: 0.13 / Net I/σ(I): 4.27
Reflection shellResolution: 2.4→2.53 Å / Redundancy: 2.91 % / Rmerge(I) obs: 0.46 / Mean I/σ(I) obs: 1.65 / % possible all: 93

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.4→48.662 Å / SU ML: 0.42 / σ(F): 1.34 / Phase error: 24.51 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2518 3315 5.1 %
Rwork0.2152 --
obs0.2171 65380 97.45 %
Solvent computationShrinkage radii: 1.11 Å / VDW probe radii: 1.3 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 71.996 Å2 / ksol: 0.343 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-3.3092 Å20 Å20 Å2
2---0.4663 Å20 Å2
3----2.8428 Å2
Refinement stepCycle: LAST / Resolution: 2.4→48.662 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8843 0 62 331 9236
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0049173
X-RAY DIFFRACTIONf_angle_d0.812461
X-RAY DIFFRACTIONf_dihedral_angle_d14.0243432
X-RAY DIFFRACTIONf_chiral_restr0.0561400
X-RAY DIFFRACTIONf_plane_restr0.0041562
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.43430.37481140.32052376X-RAY DIFFRACTION90
2.4343-2.47060.42271170.32642363X-RAY DIFFRACTION91
2.4706-2.50920.36481300.29722443X-RAY DIFFRACTION93
2.5092-2.55040.35021410.30272465X-RAY DIFFRACTION94
2.5504-2.59430.34631330.27812476X-RAY DIFFRACTION95
2.5943-2.64150.30161380.26642502X-RAY DIFFRACTION96
2.6415-2.69230.31311270.26982593X-RAY DIFFRACTION98
2.6923-2.74730.33381420.25512548X-RAY DIFFRACTION98
2.7473-2.8070.271300.25942618X-RAY DIFFRACTION99
2.807-2.87230.28571440.2622612X-RAY DIFFRACTION99
2.8723-2.94410.32461280.25942623X-RAY DIFFRACTION99
2.9441-3.02370.30581420.26292600X-RAY DIFFRACTION100
3.0237-3.11270.29361250.2672660X-RAY DIFFRACTION100
3.1127-3.21310.33121440.25392658X-RAY DIFFRACTION100
3.2131-3.32790.29661290.25132611X-RAY DIFFRACTION99
3.3279-3.46110.26171320.22942638X-RAY DIFFRACTION100
3.4611-3.61860.25181630.21442622X-RAY DIFFRACTION99
3.6186-3.80930.24341820.20062604X-RAY DIFFRACTION100
3.8093-4.04790.22951480.18442647X-RAY DIFFRACTION99
4.0479-4.36020.20921380.17222649X-RAY DIFFRACTION99
4.3602-4.79870.21061450.15042651X-RAY DIFFRACTION99
4.7987-5.49220.19271530.15782636X-RAY DIFFRACTION98
5.4922-6.91640.23241270.21062618X-RAY DIFFRACTION95
6.9164-48.67230.16851430.18492852X-RAY DIFFRACTION99
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)
10.7498-0.11820.21741.42460.70392.44540.0201-0.152-0.13720.2782-0.27640.11070.1612-0.46030.19530.2239-0.02860.03520.2994-0.00710.233411.179214.408725.8682
21.1681-0.25670.51740.2998-0.22460.58320.02960.0750.12020.0474-0.0336-0.0796-0.031-0.0359-0.00240.07250.00230.0150.1865-0.0040.16544.568832.61734.0362
30.74110.4748-0.28091.3787-0.14371.2259-0.04750.0878-0.0203-0.08230.0175-0.06750.2504-0.06160.02030.16920.0064-0.00210.1642-0.02990.154122.1896-0.273-2.8565
40.30460.07240.22580.99030.72270.69950.1251-0.1441-0.01730.2521-0.1019-0.00170.2513-0.1447-0.00760.37850.0343-0.04560.32320.08110.179229.7982-8.158732.9706
50.8442-0.05710.70461.668-0.77430.79440.16560.0402-0.006-0.1758-0.3547-0.81160.08540.34190.10680.31930.0814-0.02080.44430.19380.407257.683-14.427936.0092
61.3383-0.3883-0.13391.7892-0.24241.13230.0081-0.16920.32640.045-0.2217-0.4348-0.16930.36910.05250.3439-0.1707-0.0820.3210.09410.248846.043421.828936.0408
70.0053-0.01110.00350.0244-0.00750.0025-0.09410.1769-0.0146-0.0619-0.20070.2351-0.0645-0.1703-0.00310.6527-0.172-0.17610.84980.13730.66545.044923.7724.158
80.1351-0.1497-0.04171.1535-0.36340.4403-0.1911-0.1403-0.19760.25-0.045800.06980.1137-0.05650.87390.4487-0.19970.96370.03960.781535.0428-18.575732.6644
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1CHAIN A AND (RESSEQ -1:85)
2X-RAY DIFFRACTION2CHAIN A AND (RESSEQ 86:298)
3X-RAY DIFFRACTION3CHAIN B
4X-RAY DIFFRACTION4CHAIN C AND (RESSEQ -1:85)
5X-RAY DIFFRACTION5CHAIN C AND (RESSEQ 86:298)
6X-RAY DIFFRACTION6CHAIN D
7X-RAY DIFFRACTION7CHAIN A AND (RESSEQ 1296)
8X-RAY DIFFRACTION8CHAIN C AND (RESSEQ 1295)

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