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- PDB-4wt2: Co-crystal Structure of MDM2 in Complex with AM-7209 -

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Basic information

Entry
Database: PDB / ID: 4wt2
TitleCo-crystal Structure of MDM2 in Complex with AM-7209
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / P53 / PROTEIN-PROTEIN INTERACTION / LIGASE-LIGASE INHIBITOR complex
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 / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / 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 / response to ether / traversing start control point of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / 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 / response to iron ion / peroxisome proliferator activated receptor binding / negative regulation of protein processing / response to steroid hormone / NEDD8 ligase activity / SUMO transferase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / 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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / ligase activity / protein sumoylation / SUMOylation of transcription factors / protein localization to nucleus / cellular response to actinomycin D / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / cellular response to gamma radiation / 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 hydrogen peroxide / cellular response to growth factor stimulus / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of TP53 Degradation / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / protein ubiquitination / regulation of cell cycle / Ub-specific processing proteases / 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 / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding
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-3UD / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.42 Å
AuthorsShaffer, P.L. / Huang, X. / Yakowec, P. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2-p53 Interaction.
Authors: Rew, Y. / Sun, D. / Yan, X. / Beck, H.P. / Canon, J. / Chen, A. / Duquette, J. / Eksterowicz, J. / Fox, B.M. / Fu, J. / Gonzalez, A.Z. / Houze, J. / Huang, X. / Jiang, M. / Jin, L. / Li, Y. ...Authors: Rew, Y. / Sun, D. / Yan, X. / Beck, H.P. / Canon, J. / Chen, A. / Duquette, J. / Eksterowicz, J. / Fox, B.M. / Fu, J. / Gonzalez, A.Z. / Houze, J. / Huang, X. / Jiang, M. / Jin, L. / Li, Y. / Li, Z. / Ling, Y. / Lo, M.C. / Long, A.M. / McGee, L.R. / McIntosh, J. / Oliner, J.D. / Osgood, T. / Saiki, A.Y. / Shaffer, P. / Wang, Y.C. / Wortman, S. / Yakowec, P. / Ye, Q. / Yu, D. / Zhao, X. / Zhou, J. / Medina, J.C. / Olson, S.H.
History
DepositionOct 30, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 3, 2014Provider: repository / Type: Initial release
Revision 1.1Jan 14, 2015Group: Database references
Revision 1.2Feb 4, 2015Group: Derived calculations
Revision 1.3Nov 22, 2017Group: Database references / Derived calculations ...Database references / Derived calculations / Refinement description / Source and taxonomy
Category: citation / entity_src_gen ...citation / entity_src_gen / pdbx_struct_oper_list / software
Item: _citation.journal_id_CSD / _entity_src_gen.pdbx_alt_source_flag / _pdbx_struct_oper_list.symmetry_operation
Revision 1.4Sep 27, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)12,9854
Polymers12,0451
Non-polymers9403
Water2,144119
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)45.517, 45.517, 208.624
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122

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Components

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


Mass: 12045.075 Da / Num. of mol.: 1 / Fragment: UNP RESIDUES 12-116
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, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-3UD / 4-({[(3R,5R,6S)-1-[(1S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl]-6-(4-chloro-3-fluorophenyl)-5-(3-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]acetyl}amino)-2-methoxybenzoic acid


Mass: 747.700 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C37H41Cl2FN2O7S
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 119 / 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: 2.59 Å3/Da / Density % sol: 52.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 1.4M Ammonium Sulfate, 0.1M Sodium Citrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.1 / Wavelength: 0.97741 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Aug 31, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97741 Å / Relative weight: 1
ReflectionResolution: 1.42→50 Å / Num. obs: 25560 / % possible obs: 99.9 % / Redundancy: 14.5 % / Rmerge(I) obs: 0.065 / Χ2: 1.058 / Net I/av σ(I): 45.507 / Net I/σ(I): 8.8 / Num. measured all: 369644
Reflection shell

Diffraction-ID: 1 / Rejects: 0

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2% possible all
1.42-1.4711.60.77424590.5699.4
1.47-1.5313.80.63824530.596100
1.53-1.614.60.46324760.635100
1.6-1.6814.60.3325130.674100
1.68-1.7914.80.22225030.722100
1.79-1.93150.13725210.828100
1.93-2.1215.10.08625340.901100
2.12-2.4314.90.07625791.602100
2.43-3.0615.10.06626382.178100
3.06-50150.03228841.52299.9

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Processing

Software
NameVersionClassification
REFMAC5.7.0029refinement
HKL-2000data scaling
PDB_EXTRACT3.15data extraction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ERF

4erf


Resolution: 1.42→38.76 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.963 / SU B: 1.527 / SU ML: 0.034 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.058 / ESU R Free: 0.058 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.1919 1263 5 %RANDOM
Rwork0.1762 24178 --
obs0.177 24178 99.89 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 50.01 Å2 / Biso mean: 19.269 Å2 / Biso min: 10.91 Å2
Baniso -1Baniso -2Baniso -3
1-0.15 Å20.15 Å20 Å2
2--0.15 Å20 Å2
3----0.5 Å2
Refinement stepCycle: final / Resolution: 1.42→38.76 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms839 0 60 119 1018
Biso mean--18.58 31.16 -
Num. residues----105
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0050.02948
X-RAY DIFFRACTIONr_bond_other_d0.0020.02930
X-RAY DIFFRACTIONr_angle_refined_deg1.2332.0691301
X-RAY DIFFRACTIONr_angle_other_deg1.363.0062103
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4085113
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.37924.11834
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.72615172
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.925154
X-RAY DIFFRACTIONr_chiral_restr0.1050.2153
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211005
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02185
LS refinement shellResolution: 1.42→1.456 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.309 90 -
Rwork0.309 1683 -
all-1773 -
obs--98.94 %
Refinement TLS params.Method: refined / Origin x: 13.9369 Å / Origin y: -17.4892 Å / Origin z: -5.6715 Å
111213212223313233
T0.0343 Å2-0.0002 Å20.0042 Å2-0.0873 Å20.0405 Å2--0.0222 Å2
L0.5745 °20.3483 °2-0.1576 °2-0.8559 °2-0.1867 °2--0.7617 °2
S-0.0387 Å °0.0165 Å °0.0002 Å °-0.0541 Å °0.0254 Å °-0.0189 Å °0.0097 Å °-0.0621 Å °0.0133 Å °

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