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

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Basic information

Entry
Database: PDB / ID: 4bcm
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 / STRUCTURE-BASED DRUG DESIGN
Function / homology
Function and homology information


: / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon ...: / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / Transcription of E2F targets under negative control by p107 (RBL1) and p130 (RBL2) in complex with HDAC1 / cellular response to leptin stimulus / male pronucleus / female pronucleus / cellular response to cocaine / response to glucagon / positive regulation of DNA biosynthetic process / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / 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 / cochlea development / Telomere Extension By Telomerase / animal organ regeneration / 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 / Cajal body / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / 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 / cellular response to platelet-derived growth factor stimulus / 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 / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / 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 / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / positive regulation of fibroblast proliferation / 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 / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / Ras protein signal transduction / chromosome, telomeric region / DNA replication / protein phosphorylation / endosome / Ub-specific processing proteases / 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 / protein kinase binding
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
MONOTHIOGLYCEROL / Chem-T7Z / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.45 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 1.0Mar 6, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 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)129,9168
Polymers128,7294
Non-polymers1,1874
Water5,170287
1
A: CYCLIN-DEPENDENT KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9454
Polymers64,3512
Non-polymers5942
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3330 Å2
ΔGint-14.2 kcal/mol
Surface area23200 Å2
MethodPISA
2
C: CYCLIN-DEPENDENT KINASE 2
D: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9714
Polymers64,3782
Non-polymers5942
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3520 Å2
ΔGint-14.4 kcal/mol
Surface area22570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.070, 135.410, 148.630
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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Protein , 3 types, 4 molecules ACBD

#1: Protein CYCLIN-DEPENDENT KINASE 2 / 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: 30053.717 Da / Num. of mol.: 1 / Fragment: RESIDUES 171-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248
#3: Protein CYCLIN-A2 / CYCLIN-A


Mass: 30079.799 Da / Num. of mol.: 1 / Fragment: RESIDUES 171-432
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248

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Non-polymers , 3 types, 291 molecules

#4: Chemical ChemComp-T7Z / 4-(4-methyl-2-methylimino-3H-1,3-thiazol-5-yl)-2-[(4-methyl-3-morpholin-4-ylsulfonyl-phenyl)amino]pyrimidine-5-carbonitrile


Mass: 485.582 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C21H23N7O3S2
#5: Chemical ChemComp-SGM / MONOTHIOGLYCEROL


Mass: 108.159 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C3H8O2S
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 287 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 3 Å3/Da / Density % sol: 58 % / Description: NONE
Crystal growpH: 7
Details: COCRYSTALS WERE GROWN IN 1-1.25M AMMONIUM SULFATE, 0.5-0.9M KCL, IN THE PRESENCE OF 100MM HEPES, PH 7.0, 5MM DTT AND COMPOUND

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.979
DetectorType: ADSC CCD / Detector: CCD
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979 Å / Relative weight: 1
ReflectionResolution: 2.39→59.54 Å / Num. obs: 55186 / % possible obs: 99.3 % / Redundancy: 3.47 % / Biso Wilson estimate: 41.12 Å2 / Rmerge(I) obs: 0.11 / Net I/σ(I): 5.25
Reflection shellResolution: 2.45→2.58 Å / Redundancy: 3.52 % / Rmerge(I) obs: 0.53 / Mean I/σ(I) obs: 1.42 / % possible all: 99.7

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Processing

Software
NameVersionClassification
PHENIX(PHENIX.REFINE)refinement
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.45→52.462 Å / SU ML: 0.85 / σ(F): 1.34 / Phase error: 24.48 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.258 1999 3.6 %
Rwork0.1959 --
obs0.1981 55144 98.99 %
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Solvent model: FLAT BULK SOLVENT MODEL / Bsol: 49.742 Å2 / ksol: 0.38 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1--5.0055 Å20 Å20 Å2
2--2.8361 Å20 Å2
3---2.1693 Å2
Refinement stepCycle: LAST / Resolution: 2.45→52.462 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8739 0 78 287 9104
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0069049
X-RAY DIFFRACTIONf_angle_d0.96412285
X-RAY DIFFRACTIONf_dihedral_angle_d15.1343396
X-RAY DIFFRACTIONf_chiral_restr0.0631378
X-RAY DIFFRACTIONf_plane_restr0.0041532
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.45-2.51130.37141400.32073742X-RAY DIFFRACTION100
2.5113-2.57920.38461430.30933772X-RAY DIFFRACTION99
2.5792-2.65510.35781420.28253782X-RAY DIFFRACTION99
2.6551-2.74080.31381410.25343745X-RAY DIFFRACTION99
2.7408-2.83870.31941420.24093770X-RAY DIFFRACTION99
2.8387-2.95240.3111410.2293759X-RAY DIFFRACTION99
2.9524-3.08670.31051440.223813X-RAY DIFFRACTION99
3.0867-3.24950.25771410.19953754X-RAY DIFFRACTION99
3.2495-3.4530.26451430.18463806X-RAY DIFFRACTION100
3.453-3.71960.22091440.1763821X-RAY DIFFRACTION100
3.7196-4.09370.2231440.15543817X-RAY DIFFRACTION99
4.0937-4.68580.19451430.14583808X-RAY DIFFRACTION98
4.6858-5.90230.22761440.17063823X-RAY DIFFRACTION98
5.9023-52.47380.24931470.19543933X-RAY DIFFRACTION96
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)
10.32420.17440.05941.86710.92111.84610.0841-0.2439-0.14620.1444-0.31480.16730.1669-0.33760.13530.2078-0.0350.01150.29610.010.206310.677714.353224.3445
21.525-0.25150.58590.5945-0.36750.57030.0460.00890.1384-0.0327-0.03180.0156-0.0501-0.05620.00250.07930.00390.02570.18190.01360.19394.877631.43733.9811
31.00540.3431-0.17061.0011-0.0881.3369-0.04110.0876-0.0513-0.03350.0375-0.02010.23-0.00180.00940.15030.007-0.00710.1066-0.01590.143321.6305-0.1252-2.9672
40.62080.17770.18850.98540.63880.81120.0555-0.3283-0.13010.1623-0.11520.01460.17550.13210.03990.27560.0643-0.01890.39650.11260.163828.398-8.186731.6681
50.3191-0.2873-0.15331.0351-0.27970.2982-0.0198-0.3514-0.0950.034-0.1654-0.42260.20330.62220.1510.29810.27440.04690.93650.30380.379255.1021-14.570734.1527
60.8113-0.0057-0.13870.8617-0.07340.51180.0476-0.19080.234-0.079-0.0639-0.3498-0.31290.6883-0.02490.3435-0.40540.02580.68920.00960.252143.076819.626734.7201
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

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