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- PDB-3lbk: Structure of human MDM2 protein in complex with a small molecule ... -

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Basic information

Entry
Database: PDB / ID: 3lbk
TitleStructure of human MDM2 protein in complex with a small molecule inhibitor
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / MDMX / MDM2 / p53 / inhibitor / Alternative splicing / Cytoplasm / Nucleus / Phosphoprotein / Proto-oncogene / Ubl conjugation / Ubl conjugation pathway / Zinc-finger
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / response to ether / traversing start control point of mitotic cell cycle / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / receptor serine/threonine kinase binding ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / response to ether / traversing start control point of mitotic cell cycle / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / receptor serine/threonine kinase binding / peroxisome proliferator activated receptor binding / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / response to iron ion / atrioventricular valve morphogenesis / endocardial cushion morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / positive regulation of muscle cell differentiation / cardiac septum morphogenesis / regulation of postsynaptic neurotransmitter receptor internalization / SUMOylation of ubiquitinylation proteins / blood vessel development / ligase activity / cellular response to alkaloid / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of signal transduction by p53 class mediator / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / cellular response to UV-C / protein sumoylation / cellular response to actinomycin D / blood vessel remodeling / cellular response to estrogen stimulus / 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 / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / ubiquitin binding / response to cocaine / DNA damage response, signal transduction by p53 class mediator / Stabilization of p53 / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / Oncogene Induced Senescence / RING-type E3 ubiquitin transferase / protein destabilization / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / response to toxic substance / centriolar satellite / cellular response to hydrogen peroxide / 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 / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / apoptotic process / 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 / MDM2 / SWIB/MDM2 domain / 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 ...E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Chem-K23 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsPopowicz, G.M. / Czarna, A. / Wolf, S. / Holak, T.A.
CitationJournal: Cell Cycle / Year: 2010
Title: Structures of low molecular weight inhibitors bound to MDMX and MDM2 reveal new approaches for p53-MDMX/MDM2 antagonist drug discovery
Authors: Popowicz, G.M. / Czarna, A. / Wolf, S. / Wang, K. / Wang, W. / Domling, A. / Holak, T.A.
History
DepositionJan 8, 2010Deposition site: RCSB / Processing site: PDBJ
Revision 1.0Mar 16, 2010Provider: repository / Type: Initial release
Revision 1.1Jul 13, 2011Group: Version format compliance
Revision 1.2Nov 1, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Oct 17, 2018Group: Data collection / Database references / Category: citation
Item: _citation.page_first / _citation.page_last ..._citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed
Revision 1.4Nov 10, 2021Group: Database references / Derived calculations / Category: database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 1.5Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
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Assembly

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


Theoretical massNumber of molelcules
Total (without water)11,7173
Polymers11,1591
Non-polymers5582
Water36020
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules

A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,4356
Polymers22,3182
Non-polymers1,1174
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation5_655-x+1,y,-z1
Buried area1110 Å2
ΔGint-9 kcal/mol
Surface area9290 Å2
MethodPISA
Unit cell
Length a, b, c (Å)60.460, 60.460, 48.050
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number91
Space group name H-MP4122

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Components

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


Mass: 11159.074 Da / Num. of mol.: 1 / Fragment: p53 binding domain / Mutation: L33E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pET-46 Ek/LIC / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 DE3
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-K23 / 6-chloro-3-[1-(4-chlorobenzyl)-4-phenyl-1H-imidazol-5-yl]-1H-indole-2-carboxylic acid


Mass: 462.327 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H17Cl2N3O2
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 20 / Source method: isolated from a natural source / Formula: H2O

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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: 1.97 Å3/Da / Density % sol: 37.48 %
Crystal growTemperature: 300 K / Method: vapor diffusion, sitting drop / pH: 4.5
Details: 0.1M sodium-acetate-trihydrate, 2M ammonium sulfate, pH 4.5, VAPOR DIFFUSION, SITTING DROP, temperature 300K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: MAR CCD 165 mm / Detector: CCD / Date: May 25, 2009 / Details: monochromator, mirror
RadiationMonochromator: Si / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→30 Å / Num. all: 7896 / Num. obs: 6949 / % possible obs: 88.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.079 / Net I/σ(I): 12.1
Reflection shellResolution: 2.2→2.3 Å / Rmerge(I) obs: 0.502 / Mean I/σ(I) obs: 1.8 / % possible all: 80.4

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Processing

Software
NameVersionClassification
MAR345data collection
MOLREPphasing
REFMAC5.5.0072refinement
MOSFLMdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1RV1

1rv1


Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.926 / SU B: 6.726 / SU ML: 0.157 / Cross valid method: THROUGHOUT / σ(F): 2 / ESU R: 0.231 / ESU R Free: 0.206 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25145 323 4.7 %RANDOM
Rwork0.20745 ---
all0.21 6949 --
obs0.20942 6613 88.61 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 39.097 Å2
Baniso -1Baniso -2Baniso -3
1-1.28 Å20 Å20 Å2
2--1.28 Å20 Å2
3----2.56 Å2
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms695 0 37 20 752
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.022749
X-RAY DIFFRACTIONr_bond_other_d0.0020.02512
X-RAY DIFFRACTIONr_angle_refined_deg1.6952.0541013
X-RAY DIFFRACTIONr_angle_other_deg0.9483.0041230
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.597584
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.58622.85728
X-RAY DIFFRACTIONr_dihedral_angle_3_deg20.75615138
X-RAY DIFFRACTIONr_dihedral_angle_4_deg28.761154
X-RAY DIFFRACTIONr_chiral_restr0.0910.2110
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021787
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02145
X-RAY DIFFRACTIONr_mcbond_it0.8681.5423
X-RAY DIFFRACTIONr_mcbond_other0.1291.5170
X-RAY DIFFRACTIONr_mcangle_it1.592688
X-RAY DIFFRACTIONr_scbond_it1.8963326
X-RAY DIFFRACTIONr_scangle_it3.1694.5325
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.509 29 -
Rwork0.353 419 -
obs--80.29 %

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