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- PDB-2wev: Truncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin... -

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Basic information

Entry
Database: PDB / ID: 2wev
TitleTruncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin A Through Structure Guided Design
Components
  • ARG-ARG-B3L-MEA
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN-A2
KeywordsTRANSFERASE / CDK2 / KINASE / CYCLIN / ACTIVE / NUCLEUS / MITOSIS / SERINE/THREONINE-PROTEIN KINASE / CYTOPLASM / INHIBITION / CELL CYCLE / ATP-BINDING / CELL DIVISION / PHOSPHOPROTEIN / NUCLEOTIDE-BINDING / POLYMORPHISM / BETA-PEPTIDE / CYCLIN GROOVE
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 / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / 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 / response to glucagon ...Phosphorylation of proteins involved in the G2/M transition by Cyclin A:Cdc2 complexes / cyclin A2-CDK1 complex / cell cycle G1/S phase transition / cellular response to luteinizing hormone stimulus / mitotic cell cycle phase transition / 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 / response to glucagon / cellular response to cocaine / cyclin-dependent protein serine/threonine kinase regulator activity / cellular response to insulin-like growth factor stimulus / positive regulation of DNA biosynthetic process / cochlea development / cyclin A1-CDK2 complex / cyclin E2-CDK2 complex / cyclin E1-CDK2 complex / cellular response to platelet-derived growth factor stimulus / cyclin A2-CDK2 complex / positive regulation of DNA-templated DNA replication initiation / G2 Phase / cyclin-dependent protein kinase activity / 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 / X chromosome / PTK6 Regulates Cell Cycle / regulation of anaphase-promoting complex-dependent catabolic process / regulation of DNA replication / Defective binding of RB1 mutants to E2F1,(E2F2, E2F3) / centriole replication / Regulation of APC/C activators between G1/S and early anaphase / centrosome duplication / Telomere Extension By Telomerase / G0 and Early G1 / Activation of the pre-replicative complex / cyclin-dependent protein kinase holoenzyme complex / cellular response to nitric oxide / Cajal body / animal organ regeneration / cyclin-dependent kinase / cyclin-dependent protein serine/threonine kinase activity / Activation of ATR in response to replication stress / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / 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 / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / male germ cell nucleus / response to organic substance / cellular response to estradiol stimulus / Cdc20:Phospho-APC/C mediated degradation of Cyclin A / G1/S transition of mitotic cell cycle / potassium ion transport / DNA Damage/Telomere Stress Induced Senescence / CDK-mediated phosphorylation and removal of Cdc6 / SCF(Skp2)-mediated degradation of p27/p21 / Meiotic recombination / Orc1 removal from chromatin / Transcriptional regulation of granulopoiesis / Cyclin D associated events in G1 / positive regulation of fibroblast proliferation / G2/M transition of mitotic cell cycle / cellular senescence / Regulation of TP53 Degradation / nuclear envelope / Factors involved in megakaryocyte development and platelet production / Processing of DNA double-strand break ends / cellular response to hypoxia / Senescence-Associated Secretory Phenotype (SASP) / regulation of gene expression / peptidyl-serine phosphorylation / Ras protein signal transduction / Regulation of TP53 Activity through Phosphorylation / transcription regulator complex / DNA replication / chromosome, telomeric region / Ub-specific processing proteases / endosome / chromatin remodeling / cell division / protein domain specific binding / protein phosphorylation / DNA repair / protein serine kinase activity / centrosome / protein serine/threonine kinase activity / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription / magnesium ion binding / negative regulation of transcription by RNA polymerase II
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 / Transferase(Phosphotransferase) domain 1 / Transferase(Phosphotransferase); domain 1 / Phosphorylase Kinase; domain 1 / Phosphorylase Kinase; 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-CK7 / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsKontopidis, G. / Andrews, M.J. / McInnes, C. / Plater, A. / Innes, L. / Renachowski, S. / Cowan, A. / Fischer, P.M.
CitationJournal: Chemmedchem / Year: 2009
Title: Truncation and Optimisation of Peptide Inhibitors of Cyclin-Dependent Kinase 2-Cyclin a Through Structure-Guided Design.
Authors: Kontopidis, G. / Andrews, M.J. / Mcinnes, C. / Plater, A. / Innes, L. / Renachowski, S. / Cowan, A. / Fischer, P.M.
History
DepositionApr 1, 2009Deposition site: PDBE / Processing site: PDBE
SupersessionJun 9, 2009ID: 2C5P
Revision 1.0Jun 9, 2009Provider: repository / Type: Initial release
Revision 1.1Feb 8, 2017Group: Derived calculations / Source and taxonomy / Version format compliance
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Other
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_validate_main_chain_plane / pdbx_validate_peptide_omega / pdbx_validate_rmsd_angle / pdbx_validate_torsion / struct_conn / struct_site
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_database_status.status_code_sf / _struct_conn.pdbx_leaving_atom_flag / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 2.1Dec 13, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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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: ARG-ARG-B3L-MEA
F: ARG-ARG-B3L-MEA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)129,6348
Polymers128,9786
Non-polymers6572
Water9,818545
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
E: ARG-ARG-B3L-MEA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8174
Polymers64,4893
Non-polymers3281
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4740 Å2
ΔGint-18.6 kcal/mol
Surface area28350 Å2
MethodPISA
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
F: ARG-ARG-B3L-MEA
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,8174
Polymers64,4893
Non-polymers3281
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4680 Å2
ΔGint-16.9 kcal/mol
Surface area29450 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.523, 113.844, 158.462
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:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1115A1 - 298
2115C1 - 298
1125B175 - 432
2125D175 - 432

NCS ensembles :
ID
1
2

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Components

#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) / Cell line (production host): SF9 / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein CYCLIN-A2 / CYCLIN-A


Mass: 29867.512 Da / Num. of mol.: 2 / Fragment: RESIDUES 173-432
Source method: isolated from a genetically manipulated source
Details: CAP-TETRAPEPTIDE INHIBITOR / Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248
#3: Protein/peptide ARG-ARG-B3L-MEA


Mass: 644.834 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#4: Chemical ChemComp-CK7 / [4-(2-AMINO-4-METHYL-THIAZOL-5-YL)-PYRIMIDIN-2-YL]-(3-NITRO-PHENYL)-AMINE


Mass: 328.349 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C14H12N6O2S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 545 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer details4 ((2 AMINO 4 METHYL THIAZOL 5 YL) PYRIMIDIN 2 YL) (3 NITRO PHENYL) AMINE (CK7): CDK2 BOUND LIGAND
Sequence detailsFRACTION 172-432 CRYSTALLISED IN COMPLEX WITH CDK2

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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: 2.48 Å3/Da / Density % sol: 50.02 % / Description: NONE
Crystal growpH: 7.8 / Details: PEG3350 30% V/V, 0.1M TRI-SODIUM CITRATE, pH 7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-1 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.3→40 Å / Num. obs: 60655 / % possible obs: 96.4 % / Observed criterion σ(I): 2 / Redundancy: 4.1 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 15.7
Reflection shellResolution: 2.3→2.42 Å / Rmerge(I) obs: 0.28 / % possible all: 80.4

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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: 2.3→40 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.885 / SU B: 6.365 / SU ML: 0.159 / Cross valid method: THROUGHOUT / ESU R: 0.338 / ESU R Free: 0.241 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS.
RfactorNum. reflection% reflectionSelection details
Rfree0.2427 2926 5 %RANDOM
Rwork0.1871 ---
obs0.18992 55318 96.05 %-
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: 29.276 Å2
Baniso -1Baniso -2Baniso -3
1-1.73 Å20 Å20 Å2
2---0.92 Å20 Å2
3----0.81 Å2
Refinement stepCycle: LAST / Resolution: 2.3→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9017 0 46 545 9608
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0229347
X-RAY DIFFRACTIONr_bond_other_d0.0010.026316
X-RAY DIFFRACTIONr_angle_refined_deg1.3541.99812695
X-RAY DIFFRACTIONr_angle_other_deg0.895315458
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.79851106
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.51223.975395
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.65151617
X-RAY DIFFRACTIONr_dihedral_angle_4_deg14.8141544
X-RAY DIFFRACTIONr_chiral_restr0.0880.21425
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0210087
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021813
X-RAY DIFFRACTIONr_nbd_refined0.2190.32066
X-RAY DIFFRACTIONr_nbd_other0.210.36537
X-RAY DIFFRACTIONr_nbtor_refined0.1850.54550
X-RAY DIFFRACTIONr_nbtor_other0.0940.54448
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.20.5769
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.2150.51
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2040.323
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2090.347
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2670.526
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.21.55736
X-RAY DIFFRACTIONr_mcbond_other0.2821.52198
X-RAY DIFFRACTIONr_mcangle_it1.97429039
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.87834111
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it4.2814.53655
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

Refine-ID: X-RAY DIFFRACTION

Ens-IDDom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
11A1737medium positional0.40.5
12C1737medium positional0.40.5
21B1523medium positional0.250.5
22D1523medium positional0.250.5
11A2319loose positional0.745
12C2319loose positional0.745
21B1991loose positional0.585
22D1991loose positional0.585
11A1737medium thermal1.692
12C1737medium thermal1.692
21B1523medium thermal1.22
22D1523medium thermal1.22
11A2319loose thermal2.7210
12C2319loose thermal2.7210
21B1991loose thermal1.9710
22D1991loose thermal1.9710
LS refinement shellResolution: 2.3→2.36 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.233 128 -
Rwork0.186 3042 -
obs--72.29 %

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