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Entry
Database: PDB / ID: 2wfy
TitleTruncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin A Through Structure Guided Design
Components
  • ARG-ARG-B3L-PHE
  • 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


: / 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 / 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 / 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 / Transcriptional regulation of granulopoiesis / Orc1 removal from chromatin / 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
Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.53 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 15, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 9, 2009Provider: repository / Type: Initial release
Revision 1.1Oct 12, 2011Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Version format compliance
Revision 1.2Dec 28, 2016Group: Derived calculations / Source and taxonomy
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations / Other / Refinement description
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_ncs_dom_lim
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 / _pdbx_validate_torsion.phi / _pdbx_validate_torsion.psi / _struct_conn.pdbx_leaving_atom_flag / _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
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-PHE
F: ARG-ARG-B3L-PHE


Theoretical massNumber of molelcules
Total (without water)128,9506
Polymers128,9506
Non-polymers00
Water7,981443
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
E: ARG-ARG-B3L-PHE


Theoretical massNumber of molelcules
Total (without water)64,4753
Polymers64,4753
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-17.9 kcal/mol
Surface area24120 Å2
MethodPISA
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
F: ARG-ARG-B3L-PHE


Theoretical massNumber of molelcules
Total (without water)64,4753
Polymers64,4753
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4430 Å2
ΔGint-12.9 kcal/mol
Surface area24570 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.621, 115.813, 157.911
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

Dom-IDEns-IDBeg auth comp-IDBeg label comp-IDRefine codeAuth asym-IDLabel asym-IDAuth seq-IDLabel seq-ID
11METMET3AA1 - 2961 - 296
21METMET3CC1 - 2961 - 296
12PROPRO2BB176 - 4324 - 260
22PROPRO2DD176 - 4324 - 260

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
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
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248
#3: Protein/peptide ARG-ARG-B3L-PHE


Mass: 630.807 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 443 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsCHAINS E AND F COULD BE REPRESENTED AS A SINGLE HETEROGEN WITH NAME: (S)-3-((S)-2-((S)-2-ACETAMIDO- ...CHAINS E AND F COULD BE REPRESENTED AS A SINGLE HETEROGEN WITH NAME: (S)-3-((S)-2-((S)-2-ACETAMIDO-5-GUANIDINOPENTANAMIDO)- 5-GUANIDINOPENTANAMIDO)-N-((S)-1-AMINO-1-OXO-3- PHENYLPROPAN-2-YL)-5-METHYLHEXANAMIDE
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: SRS / Beamline: PX14.1 / Wavelength: 0.977
DetectorType: ADSC CCD / Detector: CCD / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 2.53→40 Å / Num. obs: 46387 / % possible obs: 80 % / Observed criterion σ(I): 1.3 / Redundancy: 13 % / Rmerge(I) obs: 0.3 / Net I/σ(I): 9
Reflection shellResolution: 2.53→2.56 Å / Rmerge(I) obs: 0.3 / Mean I/σ(I) obs: 1.34 / % possible all: 70

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1OKV

1okv


Resolution: 2.53→40 Å / Cor.coef. Fo:Fc: 0.954 / Cor.coef. Fo:Fc free: 0.914 / SU B: 11.747 / SU ML: 0.252 / Cross valid method: THROUGHOUT / ESU R: 0.785 / ESU R Free: 0.323 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. RESIDUES 36-40 IN CHAIN A AND C ARE DISORDERED RESIDUES 323-325 IN CHAIN B NAD D ARE DISORDERED
RfactorNum. reflection% reflectionSelection details
Rfree0.25878 880 2.1 %RANDOM
Rwork0.19328 ---
obs0.19466 41853 92.17 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 52.652 Å2
Baniso -1Baniso -2Baniso -3
1--3.49 Å20 Å20 Å2
2--1 Å20 Å2
3---2.49 Å2
Refinement stepCycle: LAST / Resolution: 2.53→40 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9017 0 0 443 9460
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0229263
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.6081.98412577
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.76451110
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.51423.995398
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.113151619
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.411544
X-RAY DIFFRACTIONr_chiral_restr0.1140.21421
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.026896
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined0.2440.34288
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined0.3270.56376
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1950.5657
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.2260.345
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1610.510
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.4111.55686
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it2.26229051
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it3.69233933
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it5.5784.53523
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
11A1179tight positional0.150.05
12C1179tight positional0.150.05
21B1026tight positional0.080.05
22D1026tight positional0.080.05
21B1044medium positional0.440.5
22D1044medium positional0.440.5
11A1179loose positional0.545
12C1179loose positional0.545
11A1179tight thermal0.410.5
12C1179tight thermal0.410.5
21B1026tight thermal0.550.5
22D1026tight thermal0.550.5
21B1044medium thermal1.362
22D1044medium thermal1.362
11A1179loose thermal2.8810
12C1179loose thermal2.8810
LS refinement shellResolution: 2.532→2.598 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.541 43 -
Rwork0.397 2615 -
obs--78.36 %

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