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- PDB-4jv9: Co-crystal structure of MDM2 with inhibitor (2S,5R,6S)-2-benzyl-5... -

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Basic information

Entry
Database: PDB / ID: 4jv9
TitleCo-crystal structure of MDM2 with inhibitor (2S,5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one
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 / traversing start control point of mitotic cell cycle / response to ether / 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 / traversing start control point of mitotic cell cycle / response to ether / 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 / peroxisome proliferator activated receptor binding / SUMO transferase activity / negative regulation of protein processing / response to iron ion / response to steroid hormone / NEDD8 ligase activity / cellular response to peptide hormone stimulus / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of protein catabolic process / blood vessel development / cardiac septum morphogenesis / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / response to magnesium ion / negative regulation of DNA damage response, signal transduction by p53 class mediator / 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 / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / ubiquitin binding / proteolysis involved in protein catabolic process / response to cocaine / Stabilization of p53 / protein destabilization / Regulation of RUNX3 expression and activity / establishment of protein localization / RING-type E3 ubiquitin transferase / cellular response to growth factor stimulus / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / ubiquitin protein ligase activity / p53 binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / negative regulation of neuron projection development / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / regulation of cell cycle / Ub-specific processing proteases / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / 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-1MO / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsHuang, X. / Gonzalez-Lopez de Turiso, F. / Sun, D. / Yosup, R. / Bartberger, M.D. / Beck, H.P. / Cannon, J. / Shaffer, P. / Oliner, J.D. / Olson, S.H. / Medina, J.C.
CitationJournal: J.Med.Chem. / Year: 2013
Title: Rational Design and Binding Mode Duality of MDM2-p53 Inhibitors.
Authors: Gonzalez-Lopez de Turiso, F. / Sun, D. / Rew, Y. / Bartberger, M.D. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Correll, T.L. / Huang, X. / Julian, L.D. / Kayser, F. / Lo, M.C. / Long, ...Authors: Gonzalez-Lopez de Turiso, F. / Sun, D. / Rew, Y. / Bartberger, M.D. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Correll, T.L. / Huang, X. / Julian, L.D. / Kayser, F. / Lo, M.C. / Long, A.M. / McMinn, D. / Oliner, J.D. / Osgood, T. / Powers, J.P. / Saiki, A.Y. / Schneider, S. / Shaffer, P. / Xiao, S.H. / Yakowec, P. / Yan, X. / Ye, Q. / Yu, D. / Zhao, X. / Zhou, J. / Medina, J.C. / Olson, S.H.
History
DepositionMar 25, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0May 1, 2013Provider: repository / Type: Initial release
Revision 1.1Jun 5, 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 / 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)11,7754
Polymers11,1561
Non-polymers6183
Water77543
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)59.848, 59.848, 75.248
Angle α, β, γ (deg.)90, 90, 90
Int Tables number92
Space group name H-MP41212
Components on special symmetry positions
IDModelComponents
11A-302-

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: 11156.052 Da / Num. of mol.: 1 / Fragment: UNP residues 18-111
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-1MO / (2S,5R,6S)-2-benzyl-5,6-bis(4-chlorophenyl)-4-methylmorpholin-3-one


Mass: 426.335 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H21Cl2NO2
#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.: 43 / 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: 3.02 Å3/Da / Density % sol: 59.27 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 7
Details: 100 mM HEPES, pH 7.0, 2.1-2.6 M ammonium sulfate, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-E DW
DetectorType: RIGAKU RAXIS IV++ / Detector: IMAGE PLATE
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 2.4→30 Å / Num. obs: 5456 / % possible obs: 94.7 % / Observed criterion σ(I): -3 / Rmerge(I) obs: 0.089
Reflection shellResolution: 2.4→2.49 Å / Rmerge(I) obs: 0.391 / % possible all: 68.7

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Processing

Software
NameClassification
CrystalCleardata collection
AMoREphasing
CNSrefinement
DENZOdata reduction
SCALEPACKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→30 Å / Occupancy max: 1 / Occupancy min: 0.5 / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.27 224 4.4 %RANDOM
Rwork0.24 4774 --
obs-4998 98 %-
Displacement parametersBiso max: 98.78 Å2 / Biso mean: 26.8926 Å2 / Biso min: 1 Å2
Baniso -1Baniso -2Baniso -3
1--1.824 Å20 Å20 Å2
2---1.824 Å20 Å2
3---3.648 Å2
Refinement stepCycle: LAST / Resolution: 2.5→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms703 0 39 43 785
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_mcbond_it1.2071.5
X-RAY DIFFRACTIONc_scbond_it2.3442
X-RAY DIFFRACTIONc_mcangle_it1.9992
X-RAY DIFFRACTIONc_scangle_it3.3852.5
Xplor file
Refine-IDSerial noParam file
X-RAY DIFFRACTION1mdm2.param
X-RAY DIFFRACTION22206093.xprm
X-RAY DIFFRACTION3MSI_CNX_TOPPAR:ion.param
X-RAY DIFFRACTION4MSI_CNX_TOPPAR:water_rep.param

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