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Basic information

Entry
Database: PDB / ID: 2uue
TitleREPLACE: A strategy for Iterative Design of Cyclin Binding Groove Inhibitors
Components
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN A2
  • GVC-TETRAPEPTIDE INHIBITOR
KeywordsTRANSFERASE/INHIBITOR / POLYMORPHISM / CYCLIN GROOVE / CELL DIVISION / CDK2 / KINASE / CYCLIN / ACTIVE / MITOSIS / INHIBITION / PHOSPHORYLATION / NUCLEOTIDE-BINDING / SERINE/THREONINE-PROTEIN KINASE / CELL CYCLE / NONPEPTIDE / TRANSFERASE / ATP-BINDING / TRANSFERASE-INHIBITOR complex
Function / homology
Function and homology information


Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / mitotic cell cycle 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 ...Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / mitotic cell cycle 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-dependent protein serine/threonine kinase regulator activity / positive regulation of DNA biosynthetic process / 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 / cyclin-dependent protein kinase activity / G2 Phase / Y chromosome / 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 / cochlea development / 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 DNA replication / Regulation of APC/C activators between G1/S and early anaphase / telomere maintenance in response to DNA damage / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / 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 / animal organ regeneration / Regulation of MITF-M-dependent genes involved in cell cycle and proliferation / Activation of ATR in response to replication stress / Cajal body / Cyclin A/B1/B2 associated events during G2/M transition / Cyclin E associated events during G1/S transition / Cyclin A:Cdk2-associated events at S phase entry / cyclin-dependent protein kinase holoenzyme complex / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / cellular response to platelet-derived growth factor stimulus / regulation of mitotic cell cycle / cellular response to nitric oxide / post-translational protein modification / cyclin binding / positive regulation of DNA replication / male germ cell nucleus / meiotic cell cycle / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / cellular response to estradiol stimulus / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / Meiotic recombination / SCF(Skp2)-mediated degradation of p27/p21 / G1/S transition of mitotic cell cycle / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / positive regulation of fibroblast proliferation / G2/M transition of mitotic cell cycle / 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 / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / Ras protein signal transduction / DNA replication / chromosome, telomeric region / endosome / Ub-specific processing proteases / chromatin remodeling / protein domain specific binding / protein phosphorylation / cell division / protein serine/threonine kinase activity / protein serine kinase activity / DNA repair / DNA-templated transcription / centrosome / positive regulation of cell population proliferation / 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, C-terminal domain / Cyclin_C / Cyclin-like ...Cyclin-A, N-terminal APC/C binding region / Cyclin-A N-terminal APC/C binding region / : / Cyclin, C-terminal domain / : / Cyclins signature. / Cyclin / Cyclin, C-terminal domain / Cyclin_C / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Phosphorylase Kinase; domain 1 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / 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-GVC / Chem-MTZ / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
synthetic construct (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.06 Å
AuthorsAndrews, M.J. / Kontopidis, G. / McInnes, C. / Plater, A. / Innes, L. / Cowan, A. / Jewsbury, P. / Fischer, P.M.
Citation
Journal: Chembiochem / Year: 2006
Title: Replace: A Strategy for Iterative Design of Cyclin- Binding Groove Inhibitors
Authors: Andrews, M.J. / Kontopidis, G. / Mcinnes, C. / Plater, A. / Innes, L. / Cowan, A. / Jewsbury, P. / Fischer, P.M.
#1: Journal: Chem.Biol. / Year: 2006
Title: Differential Binding of Inhibitors to Active and Inactive Cdk2 Provides Insights for Drug Design
Authors: Kontopidis, G. / Mcinnes, C. / Pandalaneni, S.R. / Mcnae, I. / Gibson, D. / Mezna, M. / Thomas, M. / Wood, G. / Wang, S. / Walkinshaw, M.D. / Fische, P.M.
History
DepositionMar 2, 2007Deposition site: PDBE / Processing site: PDBE
SupersessionMar 27, 2007ID: 2C5T
Revision 1.0Mar 27, 2007Provider: repository / Type: Initial release
Revision 1.1Sep 5, 2012Group: Derived calculations / Non-polymer description ...Derived calculations / Non-polymer description / Other / Version format compliance
Revision 1.2Oct 9, 2019Group: Data collection / Derived calculations ...Data collection / Derived calculations / Other / Source and taxonomy
Category: pdbx_database_status / pdbx_entity_src_syn / struct_conn
Item: _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag
Revision 1.3Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_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: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
E: GVC-TETRAPEPTIDE INHIBITOR
F: GVC-TETRAPEPTIDE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,87010
Polymers128,5896
Non-polymers1,2814
Water4,396244
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN A2
E: GVC-TETRAPEPTIDE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9355
Polymers64,2953
Non-polymers6412
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4490 Å2
ΔGint-31 kcal/mol
Surface area24060 Å2
MethodPISA
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN A2
F: GVC-TETRAPEPTIDE INHIBITOR
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,9355
Polymers64,2953
Non-polymers6412
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5110 Å2
ΔGint-24.7 kcal/mol
Surface area23500 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.563, 113.800, 155.031
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C
12B
22D

NCS domain segments:

Component-ID: 1 / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 4

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMETAA1 - 2961 - 296
21METMETCC1 - 2961 - 296
12VALVALBB175 - 4322 - 259
22VALVALDD175 - 4322 - 259

NCS ensembles :
ID
1
2

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Components

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Protein , 2 types, 4 molecules ACBD

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


Mass: 33976.488 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: TRIAZOL-1-METHYL-PYRIMIDIN INHIBITOR / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm)
References: UniProt: P24941, non-specific serine/threonine protein kinase
#2: Protein CYCLIN A2 / CYCLIN A


Mass: 29753.410 Da / Num. of mol.: 2 / Fragment: RESIDUES 174-432
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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Protein/peptide , 1 types, 2 molecules EF

#3: Protein/peptide GVC-TETRAPEPTIDE INHIBITOR


Mass: 564.697 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) synthetic construct (others)

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Non-polymers , 3 types, 248 molecules

#4: Chemical ChemComp-MTZ / 4-METHYL-5-{(2E)-2-[(4-MORPHOLIN-4-YLPHENYL)IMINO]-2,5-DIHYDROPYRIMIDIN-4-YL}-1,3-THIAZOL-2-AMINE


Mass: 368.456 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C18H20N6OS
#5: Chemical ChemComp-GVC / 1-(3,5-DICHLOROPHENYL)-5-METHYL-1H-1,2,4-TRIAZOLE-3-CARBOXYLIC ACID


Mass: 272.087 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C10H7Cl2N3O2
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 244 / Source method: isolated from a natural source / Formula: H2O

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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: 2.7 Å3/Da / Density % sol: 54 %
Crystal growpH: 7.8 / Details: 22% PEG 3350, 0.1M NA3-CIT, pH 7.80

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-2 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 14, 2003 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.06→20 Å / Num. obs: 79118 / % possible obs: 99 % / Observed criterion σ(I): 13.2 / Redundancy: 2.3 % / Rmerge(I) obs: 0.11 / Net I/σ(I): 13.2
Reflection shellResolution: 2.06→2.17 Å / Rmerge(I) obs: 1.06 / Mean I/σ(I) obs: 1.4 / % possible all: 98

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MOSFLMdata reduction
SCALAdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1OL1

1ol1


Resolution: 2.06→91.29 Å / Cor.coef. Fo:Fc: 0.958 / Cor.coef. Fo:Fc free: 0.938 / SU B: 5.172 / SU ML: 0.138 / Cross valid method: THROUGHOUT / ESU R: 0.195 / ESU R Free: 0.176 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. CHAIN A AND C RESIDUES 12-17, 37-41, 159-162
RfactorNum. reflection% reflectionSelection details
Rfree0.244 2431 3 %RANDOM
Rwork0.196 ---
obs0.197 78456 98.8 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: BABINET MODEL WITH MASK
Displacement parametersBiso mean: 54.14 Å2
Baniso -1Baniso -2Baniso -3
1--2.06 Å20 Å20 Å2
2--0.99 Å20 Å2
3---1.07 Å2
Refinement stepCycle: LAST / Resolution: 2.06→91.29 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9004 0 84 244 9332
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.010.0229322
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6361.99712664
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.90251104
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.40123.959394
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.848151616
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.7391544
X-RAY DIFFRACTIONr_chiral_restr0.1460.21422
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.026954
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2580.34410
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3320.56417
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1980.5726
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2470.340
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.3230.510
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.9951.55684
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it4.51929052
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it7.00534176
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it9.8994.53612
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
Refine LS restraints NCS

Dom-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Ens-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A2378medium positional0.410.5
2B2083medium positional0.360.5
1A2378medium thermal3.312
2B2083medium thermal2.622
LS refinement shellResolution: 2.06→2.12 Å / Total num. of bins used: 20 /
RfactorNum. reflection
Rfree0.325 200
Rwork0.28 5595

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