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

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Basic information

Entry
Database: PDB / ID: 2whb
TitleTruncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin A Through Structure Guided Design
Components
  • ARG-ARG-L3O-PFF
  • 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 / 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
Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.9 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
DepositionMay 3, 2009Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 9, 2009Provider: repository / Type: Initial release
Revision 1.1Aug 24, 2011Group: Database references / Derived calculations ...Database references / Derived calculations / Non-polymer description / Other / Refinement description / Version format compliance
Revision 1.2Feb 8, 2017Group: Source and taxonomy
Revision 2.0Apr 24, 2019Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Polymer sequence
Category: citation / citation_author ...citation / citation_author / entity_poly / pdbx_database_proc / pdbx_database_status / pdbx_seq_map_depositor_info / struct_biol / struct_conn
Item: _citation.journal_id_ISSN / _citation.page_last ..._citation.journal_id_ISSN / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.title / _citation_author.name / _entity_poly.pdbx_seq_one_letter_code_can / _pdbx_database_status.recvd_author_approval / _pdbx_seq_map_depositor_info.one_letter_code / _struct_conn.pdbx_leaving_atom_flag
Revision 2.1Dec 13, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Other / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_database_status / pdbx_initial_refinement_model / struct_conn
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_leaving_atom_flag

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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-L3O-PFF
F: ARG-ARG-L3O-PFF


Theoretical massNumber of molelcules
Total (without water)128,9666
Polymers128,9666
Non-polymers00
Water1,802100
1
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
E: ARG-ARG-L3O-PFF


Theoretical massNumber of molelcules
Total (without water)64,4833
Polymers64,4833
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4490 Å2
ΔGint-25.2 kcal/mol
Surface area29140 Å2
MethodPQS
2
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
F: ARG-ARG-L3O-PFF


Theoretical massNumber of molelcules
Total (without water)64,4833
Polymers64,4833
Non-polymers00
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area4520 Å2
ΔGint-19.7 kcal/mol
Surface area29690 Å2
MethodPQS
Unit cell
Length a, b, c (Å)74.423, 114.924, 154.468
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
1114A1 - 298
2114C1 - 298
1124B175 - 432
2124D175 - 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
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: ESCHERICHIA COLI (E. coli) / References: UniProt: P20248
#3: Protein/peptide ARG-ARG-L3O-PFF


Mass: 638.759 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.: 100 / Source method: isolated from a natural source / Formula: H2O
Nonpolymer detailsCHAINS E AND F COULD BE REPRESENTED AS A SINGLE HETEROGEN WITH NAME: (2R,3S)-N-((S)-1-AMINO-3-(4- ...CHAINS E AND F COULD BE REPRESENTED AS A SINGLE HETEROGEN WITH NAME: (2R,3S)-N-((S)-1-AMINO-3-(4-FLUOROPHENYL)-1-OXOPROPAN-2-YL) -3-((S)-2-((S)-2-AMINO-5-GUANIDINOPENTANAMIDO) -5-GUANIDINOPENTANAMIDO)-2-HYDROXY-5-METHYLHEXANAMIDE
Sequence detailsFRACTION 173-432 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: 18% V/V PEG3350 AND 0.1M SODIUM CITRATE, pH 7.8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID14-4 / Wavelength: 0.939
DetectorType: ADSC CCD / Detector: CCD / Date: Apr 16, 2004 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.939 Å / Relative weight: 1
ReflectionResolution: 2.9→30 Å / Num. obs: 29405 / % possible obs: 98 % / Observed criterion σ(I): 3 / Redundancy: 3.5 % / Rmerge(I) obs: 0.12 / Net I/σ(I): 4.4
Reflection shellResolution: 2.9→3.06 Å / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 1.6 / % possible all: 96.2

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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: 2.9→30 Å / Cor.coef. Fo:Fc: 0.935 / Cor.coef. Fo:Fc free: 0.896 / SU B: 17.356 / SU ML: 0.332 / Cross valid method: THROUGHOUT / ESU R Free: 0.444 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED REGIONS WERE MODELED STEREOCHEMICALLY CHAIN A RESIDUES 13 CHAIN B RESIDUES 175, CHAIN C RESIDUES 13, 40, 163 CHAIN D RESIDUES 323-325,402-403
RfactorNum. reflection% reflectionSelection details
Rfree0.26393 944 3.2 %RANDOM
Rwork0.18614 ---
obs0.1887 28324 97.36 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.787 Å2
Baniso -1Baniso -2Baniso -3
1--1.7 Å20 Å20 Å2
2--0.34 Å20 Å2
3---1.35 Å2
Refinement stepCycle: LAST / Resolution: 2.9→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms9013 0 0 100 9113
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0229305
X-RAY DIFFRACTIONr_bond_other_d0.0010.026347
X-RAY DIFFRACTIONr_angle_refined_deg2.5891.9912639
X-RAY DIFFRACTIONr_angle_other_deg1.2583.00315431
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.9551108
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.54323.99396
X-RAY DIFFRACTIONr_dihedral_angle_3_deg21.668151620
X-RAY DIFFRACTIONr_dihedral_angle_4_deg21.4141544
X-RAY DIFFRACTIONr_chiral_restr0.1330.21424
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0210082
X-RAY DIFFRACTIONr_gen_planes_other0.0020.021832
X-RAY DIFFRACTIONr_nbd_refined0.2530.32386
X-RAY DIFFRACTIONr_nbd_other0.2340.36597
X-RAY DIFFRACTIONr_nbtor_refined0.2130.54505
X-RAY DIFFRACTIONr_nbtor_other0.1130.54839
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.2070.5399
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1340.57
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1430.317
X-RAY DIFFRACTIONr_symmetry_vdw_other0.2080.342
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.250.55
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.3751.55708
X-RAY DIFFRACTIONr_mcbond_other0.5321.52201
X-RAY DIFFRACTIONr_mcangle_it3.71829051
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it5.56134054
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it8.1914.53586
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
11A4065medium positional0.440.5
12C4065medium positional0.440.5
21B3491medium positional0.380.5
22D3491medium positional0.380.5
11A4065medium thermal2.582
12C4065medium thermal2.582
21B3491medium thermal2.072
22D3491medium thermal2.072
LS refinement shellResolution: 2.9→2.975 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.457 56 -
Rwork0.333 2007 -
obs--94.85 %

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