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- PDB-8j81: MDM2 bound with a peptoid -

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Basic information

Entry
Database: PDB / ID: 8j81
TitleMDM2 bound with a peptoid
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / Inhibitor / Complex / Peptoid / p53-binding protein
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / peroxisome proliferator activated receptor binding / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to iron ion / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / response to steroid hormone / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / cardiac septum morphogenesis / blood vessel development / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / protein sumoylation / cellular response to UV-C / cellular response to estrogen stimulus / blood vessel remodeling / cellular response to actinomycin D / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / positive regulation of mitotic cell cycle / regulation of heart rate / DNA damage response, signal transduction by p53 class mediator / proteolysis involved in protein catabolic process / ubiquitin binding / positive regulation of protein export from nucleus / Stabilization of p53 / response to cocaine / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / protein destabilization / cellular response to growth factor stimulus / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / centriolar satellite / cellular response to hydrogen peroxide / response to toxic substance / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / p53 binding / endocytic vesicle membrane / ubiquitin protein ligase activity / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / 5S rRNA binding / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / postsynaptic density / Ub-specific processing proteases / protein ubiquitination / protein domain specific binding / response to xenobiotic stimulus / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / positive regulation of cell population proliferation / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / glutamatergic synapse / enzyme binding
Similarity search - Function
E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Zn-finger in Ran binding protein and others / Zinc finger, C3HC4 type (RING finger) / Zinc finger RanBP2 type profile. ...E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Zn-finger in Ran binding protein and others / Zinc finger, C3HC4 type (RING finger) / Zinc finger RanBP2 type profile. / Zinc finger, RanBP2-type superfamily / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
: / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.35 Å
AuthorsYokomine, M. / Fukuda, Y. / Ago, H. / Matsuura, H. / Ueno, G. / Nagatoishi, S. / Yamamoto, M. / Tsumoto, K. / Jumpei, M. / Sando, S.
Funding support Japan, 4items
OrganizationGrant numberCountry
Japan Agency for Medical Research and Development (AMED)JP21am0101070 Japan
Japan Science and TechnologyJPMJCR21N5 Japan
Japan Science and TechnologyJPMJPR21AF Japan
Japan Agency for Medical Research and Development (AMED)JP22ama121033 Japan
CitationJournal: Chem Sci / Year: 2024
Title: A high-resolution structural characterization and physicochemical study of how a peptoid binds to an oncoprotein MDM2.
Authors: Yokomine, M. / Morimoto, J. / Fukuda, Y. / Ueda, T. / Takeuchi, K. / Umezawa, K. / Ago, H. / Matsuura, H. / Ueno, G. / Senoo, A. / Nagatoishi, S. / Tsumoto, K. / Sando, S.
History
DepositionApr 28, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 1, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: Database references / Structure summary / Category: citation / citation_author / pdbx_entry_details
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year / _pdbx_entry_details.has_protein_modification

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,6089
Polymers11,5101
Non-polymers1,0988
Water1,47782
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: isothermal titration calorimetry, surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area140 Å2
ΔGint-11 kcal/mol
Surface area5490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)39.521, 45.815, 63.790
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Space group name HallP2ac2ab
Symmetry operation#1: x,y,z
#2: x+1/2,-y+1/2,-z
#3: -x,y+1/2,-z+1/2
#4: -x+1/2,-y,z+1/2

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Components

#1: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / RING-type E3 ubiquitin transferase Mdm2 / p53- ...Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / RING-type E3 ubiquitin transferase Mdm2 / p53-binding protein Mdm2


Mass: 11510.455 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-UAC / (2S)-2-[[(2S)-2-[(6-chloranyl-1H-indol-3-yl)methyl-[(2S)-2-[[(2S)-2-[ethanoyl-(phenylmethyl)amino]propanoyl]-methyl-amino]propanoyl]amino]propanoyl]-methyl-amino]-N-(3,3-dimethylbutyl)-N-[(2S)-1-oxidanylidene-1-piperazin-1-yl-propan-2-yl]propanamide


Mass: 849.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C45H65ClN8O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 82 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.51 Å3/Da / Density % sol: 50.97 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 1M Sodium Acetate trihydrate pH4.5, 3.0 M Sodium Chrolide. Peptoid dissolved in DMSO was included. The final DMSO concentration was 2.4%

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL32XU / Wavelength: 1 Å
DetectorType: DECTRIS EIGER X 9M / Detector: PIXEL / Date: Jan 25, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.29→37.21 Å / Num. obs: 54705 / % possible obs: 98.1 % / Redundancy: 6.01 % / Biso Wilson estimate: 17.7 Å2 / CC1/2: 0.999 / Rrim(I) all: 0.066 / Net I/σ(I): 13.66
Reflection shellResolution: 1.29→1.37 Å / Redundancy: 2.86 % / Num. unique obs: 7938 / CC1/2: 0.504 / % possible all: 98.1

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
XDSdata reduction
XSCALEdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.35→37.21 Å / SU ML: 0.1495 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 18.2507
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1896 3372 6.87 %
Rwork0.1692 45677 -
obs0.1706 49049 99.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 19.95 Å2
Refinement stepCycle: LAST / Resolution: 1.35→37.21 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms713 0 61 82 856
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0054876
X-RAY DIFFRACTIONf_angle_d0.89721202
X-RAY DIFFRACTIONf_chiral_restr0.0703133
X-RAY DIFFRACTIONf_plane_restr0.0072150
X-RAY DIFFRACTIONf_dihedral_angle_d25.8861356
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.35-1.370.36421370.35041827X-RAY DIFFRACTION96.89
1.37-1.390.26841410.29551893X-RAY DIFFRACTION99.51
1.39-1.410.27791390.26191933X-RAY DIFFRACTION99.95
1.41-1.430.22661350.22721892X-RAY DIFFRACTION100
1.43-1.460.23031420.19671891X-RAY DIFFRACTION100
1.46-1.490.1931380.19171923X-RAY DIFFRACTION100
1.49-1.510.22071470.18811935X-RAY DIFFRACTION100
1.51-1.550.22271360.19331866X-RAY DIFFRACTION99.95
1.55-1.580.20321440.18231915X-RAY DIFFRACTION100
1.58-1.620.22491390.18151884X-RAY DIFFRACTION100
1.62-1.660.15491420.16931923X-RAY DIFFRACTION100
1.66-1.70.1571380.16761912X-RAY DIFFRACTION100
1.7-1.750.18751390.15281905X-RAY DIFFRACTION99.9
1.75-1.810.19291400.1631905X-RAY DIFFRACTION99.85
1.81-1.870.18181430.16891928X-RAY DIFFRACTION100
1.87-1.950.18951360.16731889X-RAY DIFFRACTION100
1.95-2.040.15621400.15961921X-RAY DIFFRACTION100
2.04-2.140.18121390.15991909X-RAY DIFFRACTION100
2.14-2.280.18211420.15771907X-RAY DIFFRACTION100
2.28-2.450.21021410.16891907X-RAY DIFFRACTION100
2.45-2.70.17351440.18131905X-RAY DIFFRACTION100
2.7-3.090.18081440.17381894X-RAY DIFFRACTION100
3.09-3.890.18181440.15231894X-RAY DIFFRACTION99.85
3.89-37.210.1941420.15531919X-RAY DIFFRACTION99.9

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