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- PDB-4ogn: Co-Crystal Structure of MDM2 with Inhbitor Compound 3 -

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Basic information

Entry
Database: PDB / ID: 4ogn
TitleCo-Crystal Structure of MDM2 with Inhbitor Compound 3
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 / endocytic vesicle membrane / p53 binding / 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-2U5 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.377 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 16, 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
Item: _software.classification / _software.contact_author ..._software.classification / _software.contact_author / _software.contact_author_email / _software.date / _software.language / _software.location / _software.name / _software.type / _software.version
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)12,8954
Polymers12,0451
Non-polymers8503
Water2,684149
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 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-2U5 / 6-{[(3R,5R,6S)-1-[(1S)-2-(tert-butylsulfonyl)-1-cyclopropylethyl]-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyl-2-oxopiperidin-3-yl]methyl}pyridine-3-carboxylic acid


Mass: 657.647 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C34H38Cl2N2O5S
#3: Chemical ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 149 / 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: 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: RAYONIX MX-300 / Detector: CCD / Date: Nov 20, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.377→50 Å / Num. obs: 25881 / % possible obs: 99.8 % / Redundancy: 13.1 % / Rmerge(I) obs: 0.097 / Χ2: 1.057 / Net I/σ(I): 7.2
Reflection shell
Resolution (Å)Redundancy (%)Num. unique allΧ2Diffraction-ID% possible allRmerge(I) obs
1.377-1.4513.224970.6751100
1.45-1.5113.725020.73711000.711
1.51-1.5813.725310.79611000.516
1.58-1.6613.725190.87511000.366
1.66-1.7613.725471.02611000.259
1.76-1.913.725531.161199.90.169
1.9-2.0913.625731.26111000.121
2.09-2.3913.426031.362199.90.106
2.39-3.0212.526661.354199.70.086
3.02-5010.228901.354198.70.082

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Processing

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

4erf


Resolution: 1.377→38.734 Å / Occupancy max: 1 / Occupancy min: 0.44 / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.35 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2225 1280 4.97 %Random
Rwork0.1935 ---
obs0.1948 25776 92.86 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 56.86 Å2 / Biso mean: 20.6255 Å2 / Biso min: 10.07 Å2
Refinement stepCycle: LAST / Resolution: 1.377→38.734 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms804 0 54 149 1007
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
10.96390.341-0.77861.40510.32010.90450.0406-0.14370.06370.01460.01690.2073-0.0999-0.1456-0.01860.02090.0254-0.00520.15980.06770.087714.4908-22.954.0759
20.5431-0.3298-0.51761.8153-0.45730.9396-0.04310.2456-0.0679-0.2439-0.00310.39780.0331-0.0926-0.27760.083-0.00780.03950.22790.12050.034611.4968-15.5961-7.7808
31.58010.85630.08741.9694-0.8570.6012-0.08360.1764-0.2451-0.36920.0902-0.16110.1723-0.0258-0.0640.0705-0.02110.01350.21540.03250.069719.7242-21.9467-7.1324
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1chain 'A' and (resid 12 through 22 )A0
2X-RAY DIFFRACTION2chain 'A' and (resid 23 through 86 )A0
3X-RAY DIFFRACTION3chain 'A' and (resid 87 through 110 )A0

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