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- PDB-4odf: Co-Crystal Structure of MDM2 with Inhibitor Compound 47 -

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Basic information

Entry
Database: PDB / ID: 4odf
TitleCo-Crystal Structure of MDM2 with Inhibitor Compound 47
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 / 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 / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / 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 / protein destabilization / RING-type E3 ubiquitin transferase / 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 / Ub-specific processing proteases / postsynaptic density / 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-2U1 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2006 Å
AuthorsShaffer, P.L. / Huang, X. / Yakowec, P. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres.
Authors: Gonzalez, A.Z. / Li, Z. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Duquette, J. / Eksterowicz, J. / Fox, B.M. / Fu, J. / Huang, X. / Houze, J. / Jin, L. / Li, Y. / Ling, Y. / Lo, M.C. ...Authors: Gonzalez, A.Z. / Li, Z. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Duquette, J. / Eksterowicz, J. / Fox, B.M. / Fu, J. / Huang, X. / Houze, J. / Jin, L. / Li, Y. / Ling, Y. / Lo, M.C. / Long, A.M. / McGee, L.R. / McIntosh, J. / Oliner, J.D. / Osgood, T. / Rew, Y. / Saiki, A.Y. / Shaffer, P. / Wortman, S. / Yakowec, P. / Yan, X. / Ye, Q. / Yu, D. / Zhao, X. / Zhou, J. / Olson, S.H. / Sun, D. / Medina, J.C.
History
DepositionJan 10, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2014Group: Database references
Revision 1.2Nov 22, 2017Group: Refinement description / Category: software
Revision 1.3Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)12,7052
Polymers12,0451
Non-polymers6601
Water724
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)44.211, 44.211, 208.882
Angle α, β, γ (deg.)90.00, 90.00, 120.00
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 6-110
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-2U1 / 6-{[(2S,5R,6R)-4-[(1S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl]-6-(3-chlorophenyl)-5-(4-chlorophenyl)-2-methyl-3-oxomorpholin-2-yl]methyl}pyridine-3-carboxylic acid


Mass: 659.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C33H36Cl2N2O6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 4 / 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: 2.45 Å3/Da / Density % sol: 49.72 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 0.8-1.8M Ammonium Sulfate, 0.1M sodium Citrate, pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 22-ID / Wavelength: 1 Å
DetectorType: MARMOSAIC 300 mm CCD / Detector: CCD / Date: Oct 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.2→50 Å / Num. obs: 6540 / % possible obs: 93.2 % / Redundancy: 7 % / Rmerge(I) obs: 0.18 / Χ2: 1.852 / Net I/σ(I): 4.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.2-2.286.10.8795590.942184.8
2.28-2.376.70.8156060.954191
2.37-2.487.10.7896361.01192.2
2.48-2.617.80.7056191.096192.4
2.61-2.777.50.5536471.204194.9
2.77-2.997.60.3756461.492195.1
2.99-3.297.40.2766681.982196.5
3.29-3.767.20.1646802.818195.6
3.76-4.746.70.1156953.475195.7
4.74-506.10.0827843.194193

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Processing

Software
NameVersionClassificationNB
DENZOdata reduction
SCALEPACKdata scaling
PHENIX1.8_1069refinement
PDB_EXTRACT3.14data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry 4ERF

4erf


Resolution: 2.2006→34.814 Å / Occupancy max: 1 / Occupancy min: 0 / FOM work R set: 0.6773 / SU ML: 0.28 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Phase error: 34.97 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.3048 279 4.4 %Random
Rwork0.2616 ---
obs0.2635 6345 93.01 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 89.46 Å2 / Biso mean: 36.9346 Å2 / Biso min: 15.95 Å2
Refinement stepCycle: LAST / Resolution: 2.2006→34.814 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms789 0 44 4 837
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.006876
X-RAY DIFFRACTIONf_angle_d1.1931200
X-RAY DIFFRACTIONf_chiral_restr0.075142
X-RAY DIFFRACTIONf_plane_restr0.005144
X-RAY DIFFRACTIONf_dihedral_angle_d15.216338
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 2

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.2006-2.77230.39961280.33122866299491
2.7723-34.8180.28161510.24413200335195
Refinement TLS params.Method: refined / Origin x: 13.127 Å / Origin y: -17.0897 Å / Origin z: -6.297 Å
111213212223313233
T0.145 Å2-0.0164 Å20.071 Å2-0.328 Å20.1514 Å2--0.1009 Å2
L4.1529 °2-1.9754 °2-0.6863 °2-3.7501 °2-3.3032 °2--5.6647 °2
S0.1017 Å °0.0986 Å °0.056 Å °-0.255 Å °-0.286 Å °-0.1017 Å °-0.0017 Å °-0.2988 Å °-0.2974 Å °
Refinement TLS groupSelection details: chain 'A' and (resid 12 through 110 )

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