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- PDB-4hg7: Crystal Structure of an MDM2/Nutlin-3a complex -

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Basic information

Entry
Database: PDB / ID: 4hg7
TitleCrystal Structure of an MDM2/Nutlin-3a complex
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / MDM2 / Nutlin-3a / Surface Entropy Reduction / Mutant Validation
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 / negative regulation of signal transduction by p53 class mediator / fibroblast activation / atrial septum development / receptor serine/threonine kinase binding ...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 / negative regulation of signal transduction by p53 class mediator / fibroblast activation / atrial septum development / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / positive regulation of vascular associated smooth muscle cell migration / peroxisome proliferator activated receptor binding / SUMO transferase activity / negative regulation of protein processing / response to iron ion / response to steroid hormone / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / cellular response to alkaloid / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / ligase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / protein sumoylation / protein localization to nucleus / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / cellular response to actinomycin D / ribonucleoprotein complex binding / positive regulation of vascular associated smooth muscle cell proliferation / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / proteolysis involved in protein catabolic process / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to gamma radiation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / cellular response to hypoxia / 5S rRNA binding / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / Ub-specific processing proteases / regulation of cell cycle / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / nucleolus / negative regulation of apoptotic process / enzyme binding / negative regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm
Similarity search - Function
MDM2 / SWIB/MDM2 domain / 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 ...MDM2 / SWIB/MDM2 domain / 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 signature. / Zinc finger, RanBP2-type superfamily / 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-NUT / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.6 Å
AuthorsNoble, M.E.M. / Anil, B. / Riedinger, C. / Endicott, J.A.
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2013
Title: The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.
Authors: Anil, B. / Riedinger, C. / Endicott, J.A. / Noble, M.E.
History
DepositionOct 7, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_struct_special_symmetry / 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)11,7603
Polymers11,0821
Non-polymers6782
Water1,74797
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)23,5196
Polymers22,1642
Non-polymers1,3554
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation12_564x,x-y+1,-z-1/61
Buried area1170 Å2
ΔGint-9 kcal/mol
Surface area10140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)71.450, 71.450, 104.204
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number179
Space group name H-MP6522
Components on special symmetry positions
IDModelComponents
11A-322-

HOH

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Components

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


Mass: 11081.952 Da / Num. of mol.: 1 / Fragment: p53 binding domain (residues 17-125) / Mutation: E69A, K70A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pGEX6P1 / 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-NUT / 4-({(4S,5R)-4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one / Nutlin 3a


Mass: 581.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H30Cl2N4O4
#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.: 97 / 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: 3.46 Å3/Da / Density % sol: 64.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.6
Details: 0.5 M ammonium sulfate, 0.1 M sodium citrate, 1.0 M lithium sulfate, pH 5.6, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 298 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.8726 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Nov 26, 2010
RadiationMonochromator: Si 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.8726 Å / Relative weight: 1
ReflectionResolution: 1.6→33.79 Å / Num. obs: 21274 / % possible obs: 99.5 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 2
Reflection shellResolution: 1.6→1.69 Å / % possible all: 99.5

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASERphasing
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.6→30.94 Å / Cor.coef. Fo:Fc: 0.955 / Cor.coef. Fo:Fc free: 0.934 / SU B: 2.668 / SU ML: 0.043 / Cross valid method: THROUGHOUT / σ(F): 0.2 / ESU R: 0.081 / ESU R Free: 0.076 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.21466 1065 5 %RANDOM
Rwork0.17348 ---
obs0.17558 20070 98.75 %-
all-21397 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.609 Å2
Baniso -1Baniso -2Baniso -3
1--0.55 Å2-0.28 Å20 Å2
2---0.55 Å20 Å2
3---0.83 Å2
Refinement stepCycle: LAST / Resolution: 1.6→30.94 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms744 0 45 97 886
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.02862
X-RAY DIFFRACTIONr_bond_other_d
X-RAY DIFFRACTIONr_angle_refined_deg1.5962.0631181
X-RAY DIFFRACTIONr_angle_other_deg
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0395108
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.64724.28635
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.27715165
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.794154
X-RAY DIFFRACTIONr_chiral_restr0.0850.2132
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.021646
X-RAY DIFFRACTIONr_gen_planes_other
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr4.4813861
X-RAY DIFFRACTIONr_sphericity_free28.475547
X-RAY DIFFRACTIONr_sphericity_bonded13.9515894
LS refinement shellResolution: 1.6→1.641 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.306 61 -
Rwork0.236 1299 -
obs--98.84 %

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