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- PDB-2x1n: Truncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin... -

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Basic information

Entry
Database: PDB / ID: 2x1n
TitleTruncation and Optimisation of Peptide Inhibitors of CDK2, Cyclin A Through Structure Guided Design
Components
  • ACE-LEU-ASN-PFF-NH2
  • CELL DIVISION PROTEIN KINASE 2
  • CYCLIN-A2
KeywordsCELL CYCLE / INHIBITION / TRANSFERASE / SERINE/THREONINE-PROTEIN KINASE / CELL DIVISION
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 / 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 / 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 / cellular response to cocaine / response to glucagon / 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 / cyclin-dependent kinase / animal organ regeneration / cyclin-dependent protein serine/threonine kinase activity / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / 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 / condensed chromosome / mitotic G1 DNA damage checkpoint signaling / regulation of mitotic cell cycle / regulation of G2/M transition of mitotic cell cycle / cyclin binding / post-translational protein modification / meiotic cell cycle / positive regulation of DNA replication / 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 / G2/M transition of mitotic cell cycle / positive regulation of fibroblast proliferation / 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 / protein serine/threonine kinase activity / centrosome / DNA-templated transcription / positive regulation of cell population proliferation / protein kinase binding / positive regulation of DNA-templated transcription
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-X1N / Cyclin-A2 / Cyclin-dependent kinase 2
Similarity search - Component
Biological speciesHOMO SAPIENS (human)
SYNTHETIC CONSTRUCT (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.75 Å
AuthorsKontopidis, G. / Andrews, M.J. / McInnes, C. / Plater, A. / Innes, L. / Renachowski, S. / Cowan, A. / Fischer, P.M. / McIntyre, N.A. / Griffiths, G. ...Kontopidis, G. / Andrews, M.J. / McInnes, C. / Plater, A. / Innes, L. / Renachowski, S. / Cowan, A. / Fischer, P.M. / McIntyre, N.A. / Griffiths, G. / Barnett, A.L. / Slawin, A.M.Z. / Jackson, W. / Thomas, M. / Zheleva, D.I. / Wang, S. / Blake, D.G. / Westwood, N.J.
Citation
Journal: J.Med.Chem. / Year: 2010
Title: Design, Synthesis, and Evaluation of 2-Methyl- and 2-Amino-N-Aryl-4,5-Dihydrothiazolo[4,5-H]Quinazolin-8-Amines as Ring-Constrained 2-Anilino-4-(Thiazol-5-Yl)Pyrimidine Cyclin-Dependent Kinase Inhibitors.
Authors: Mcintyre, N.A. / Mcinnes, C. / Griffiths, G. / Barnett, A.L. / Kontopidis, G. / Slawin, A.M.Z. / Jackson, W. / Thomas, M. / Zheleva, D.I. / Wang, S. / Blake, D.G. / Westwood, N.J. / Fischer, P.M.
#1: Journal: 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
DepositionDec 31, 2009Deposition site: PDBE / Processing site: PDBE
SupersessionFeb 16, 2010ID: 2WHA
Revision 1.0Feb 16, 2010Provider: repository / Type: Initial release
Revision 1.1Dec 14, 2016Group: Source and taxonomy / Version format compliance
Revision 1.2Mar 29, 2017Group: Other
Revision 1.3Dec 20, 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 / 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_leaving_atom_flag / _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
H: ACE-LEU-ASN-PFF-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)128,9997
Polymers128,3215
Non-polymers6792
Water1,54986
1
C: CELL DIVISION PROTEIN KINASE 2
D: CYCLIN-A2
H: ACE-LEU-ASN-PFF-NH2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,7174
Polymers64,3783
Non-polymers3391
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3860 Å2
ΔGint-14.6 kcal/mol
Surface area24520 Å2
MethodPISA
2
A: CELL DIVISION PROTEIN KINASE 2
B: CYCLIN-A2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,2833
Polymers63,9432
Non-polymers3391
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3430 Å2
ΔGint-16 kcal/mol
Surface area23940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)74.558, 114.257, 157.277
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
1113A1 - 298
2113C1 - 298
1123B175 - 432
2123D175 - 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
Source: (gene. exp.) HOMO SAPIENS (human) / Production host: SPODOPTERA FRUGIPERDA (fall armyworm) / References: UniProt: P24941, EC: 2.7.1.37
#2: Protein CYCLIN-A2 / CYCLIN-A


Mass: 29966.643 Da / Num. of mol.: 2 / Fragment: RESIDUES 172-432
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 ACE-LEU-ASN-PFF-NH2


Mass: 434.486 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) SYNTHETIC CONSTRUCT (others)
#4: Chemical ChemComp-X1N / 2-METHYL-N-[(1Z)-3-NITROCYCLOHEXA-2,4-DIEN-1-YLIDENE]-4,5-DIHYDRO[1,3]THIAZOLO[4,5-H]QUINAZOLIN-8-AMINE


Mass: 339.372 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H13N5O2S
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 86 / Source method: isolated from a natural source / Formula: H2O
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 20% 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: ID14-2 / Wavelength: 0.933
DetectorType: ADSC CCD / Detector: CCD / Date: Feb 12, 2003 / Details: MIRRORS
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.933 Å / Relative weight: 1
ReflectionResolution: 2.75→30 Å / Num. obs: 37669 / % possible obs: 98.3 % / Observed criterion σ(I): 3 / Redundancy: 3.8 % / Rmerge(I) obs: 0.14 / Net I/σ(I): 12.7
Reflection shellResolution: 2.75→2.9 Å / Rmerge(I) obs: 0.67 / Mean I/σ(I) obs: 1.9 / % possible all: 98.8

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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: 2.75→30 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.889 / SU B: 14.482 / SU ML: 0.287 / Cross valid method: THROUGHOUT / ESU R Free: 0.37 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS. DISORDERED REGIONS WERE MODELED STEREOCHEMICALLY CHAIN A RES 13-15, 37-39, CHAIN C RES 13-14, 38-40
RfactorNum. reflection% reflectionSelection details
Rfree0.25478 1097 3.1 %RANDOM
Rwork0.19964 ---
obs0.20136 33849 98.01 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 34.816 Å2
Baniso -1Baniso -2Baniso -3
1--2.38 Å20 Å20 Å2
2---0.22 Å20 Å2
3---2.6 Å2
Refinement stepCycle: LAST / Resolution: 2.75→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8956 0 48 86 9090
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0229266
X-RAY DIFFRACTIONr_bond_other_d0.0060.026310
X-RAY DIFFRACTIONr_angle_refined_deg1.5481.98712592
X-RAY DIFFRACTIONr_angle_other_deg1.129315427
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.16751112
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.97523.904397
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.507151628
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.1621546
X-RAY DIFFRACTIONr_chiral_restr0.0920.21418
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0210056
X-RAY DIFFRACTIONr_gen_planes_other0.0070.021820
X-RAY DIFFRACTIONr_nbd_refined0.2190.31850
X-RAY DIFFRACTIONr_nbd_other0.2270.36175
X-RAY DIFFRACTIONr_nbtor_refined0.1890.54495
X-RAY DIFFRACTIONr_nbtor_other0.090.54768
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1820.5303
X-RAY DIFFRACTIONr_xyhbond_nbd_other0.1840.51
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1930.38
X-RAY DIFFRACTIONr_symmetry_vdw_other0.3770.328
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.2530.57
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it2.2841.55707
X-RAY DIFFRACTIONr_mcbond_other0.4731.52201
X-RAY DIFFRACTIONr_mcangle_it3.21829058
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it5.52434053
X-RAY DIFFRACTIONr_scbond_other
X-RAY DIFFRACTIONr_scangle_it7.7344.53530
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
11A1734tight positional0.20.05
12C1734tight positional0.20.05
21B1521tight positional0.150.05
22D1521tight positional0.150.05
11A2285loose positional0.595
12C2285loose positional0.595
21B1973loose positional0.55
22D1973loose positional0.55
11A1734tight thermal0.490.5
12C1734tight thermal0.490.5
21B1521tight thermal0.430.5
22D1521tight thermal0.430.5
11A2285loose thermal2.8810
12C2285loose thermal2.8810
21B1973loose thermal2.7910
22D1973loose thermal2.7910
LS refinement shellResolution: 2.75→2.821 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.373 76 -
Rwork0.328 2486 -
obs--99.07 %

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