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- PDB-1rv1: CRYSTAL STRUCTURE OF HUMAN MDM2 WITH AN IMIDAZOLINE INHIBITOR -

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Basic information

Entry
Database: PDB / ID: 1rv1
TitleCRYSTAL STRUCTURE OF HUMAN MDM2 WITH AN IMIDAZOLINE INHIBITOR
ComponentsUbiquitin-protein ligase E3 Mdm2
KeywordsLIGASE / MDM2 / P53 / PROTEIN-PROTEIN INTERACTION
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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator ...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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / peroxisome proliferator activated receptor binding / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to iron ion / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / response to steroid hormone / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / cardiac septum morphogenesis / blood vessel development / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / protein sumoylation / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / cellular response to actinomycin D / 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 / DNA damage response, signal transduction by p53 class mediator / proteolysis involved in protein catabolic process / ubiquitin binding / positive regulation of protein export from nucleus / Stabilization of p53 / response to cocaine / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / protein destabilization / cellular response to growth factor stimulus / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / centriolar satellite / cellular response to hydrogen peroxide / response to toxic substance / 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 / proteasome-mediated ubiquitin-dependent protein catabolic process / amyloid fibril formation / regulation of cell cycle / postsynaptic density / Ub-specific processing proteases / protein ubiquitination / protein domain specific binding / response to xenobiotic stimulus / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / positive regulation of cell population proliferation / 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-IMZ / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsLukacs, C. / Kammlott, U. / Graves, B.
CitationJournal: Science / Year: 2004
Title: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Authors: Vassilev, L.T. / Vu, B.T. / Graves, B. / Carvajal, D. / Podlaski, F. / Filipovic, Z. / Kong, N. / Kammlott, U. / Lukacs, C. / Klein, C. / Fotouhi, N. / Liu, E.A.
History
DepositionDec 12, 2003Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jan 20, 2004Provider: repository / Type: Initial release
Revision 1.1Apr 29, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Oct 27, 2021Group: Database references / Derived calculations / Category: 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
Revision 1.4Aug 23, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Ubiquitin-protein ligase E3 Mdm2
B: Ubiquitin-protein ligase E3 Mdm2
C: Ubiquitin-protein ligase E3 Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6158
Polymers30,1833
Non-polymers3,4325
Water55831
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)122.264, 39.727, 79.362
Angle α, β, γ (deg.)90.00, 114.29, 90.00
Int Tables number5
Space group name H-MC121

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Components

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


Mass: 10060.845 Da / Num. of mol.: 3 / Fragment: RESIDUES 25-109 / Mutation: L33E
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pQE40 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical
ChemComp-IMZ / CIS-[4,5-BIS-(4-BROMOPHENYL)-2-(2-ETHOXY-4-METHOXYPHENYL)-4,5-DIHYDROIMIDAZOL-1-YL]-[4-(2-HYDROXYETHYL)PIPERAZIN-1-YL]METHANONE


Mass: 686.434 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C31H34Br2N4O4
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 31 / 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: 2.91 Å3/Da / Density % sol: 57.72 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 7.8
Details: 54% SATD, AMMONIUM SULFATE, 2.5% PEG 200, 50mM GLUCOSE, 5mM DTT, 100mM TRIS, pH 7.8, VAPOR DIFFUSION, HANGING DROP, temperature 278K
Crystal grow
*PLUS
Method: vapor diffusion, hanging drop
Components of the solutions
*PLUS
IDConc.Common nameCrystal-IDSol-IDDetails
110 mg/mlprotein1drop
254 %satammonium sulfate1reservoir
3100 mMTris1reservoirpH7.8
42.5 %PEG2001reservoir
550 mMglucose1reservoir
65 mMdithiothreitol1reservoir

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X8C / Wavelength: 1.1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: May 4, 2002
RadiationMonochromator: Si 111 / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.1 Å / Relative weight: 1
ReflectionResolution: 2.3→50 Å / Num. all: 15502 / Num. obs: 15502 / % possible obs: 97.7 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.6 % / Biso Wilson estimate: 41.7 Å2 / Rmerge(I) obs: 0.054 / Net I/σ(I): 16
Reflection shellResolution: 2.3→2.38 Å / Redundancy: 3.47 % / Rmerge(I) obs: 0.249 / Mean I/σ(I) obs: 5.4 / Num. unique all: 1515 / % possible all: 96.4

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Processing

Software
NameVersionClassification
HKL-2000data collection
SCALEPACKdata scaling
MOLREPphasing
CNX2000.1refinement
HKL-2000data reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1YCR

1ycr


Resolution: 2.3→20 Å / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflectionSelection details
Rfree0.322 784 RANDOM
Rwork0.256 --
obs0.266 15376 -
all-15376 -
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2121 0 205 31 2357
Refine LS restraints
Refine-IDTypeDev ideal
X-RAY DIFFRACTIONc_angle_deg1.5388
X-RAY DIFFRACTIONc_bond_d0.0089
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkRefine-IDNum. reflection obsTotal num. of bins used
2.3-2.350.4039220.3598X-RAY DIFFRACTION97915
2.35-2.410.48479430.3851X-RAY DIFFRACTION99315
2.41-2.480.41479880.3431X-RAY DIFFRACTION103515
2.48-2.550.34489340.3348X-RAY DIFFRACTION98615
2.55-2.630.33319570.3227X-RAY DIFFRACTION99715
2.63-2.730.46559630.3151X-RAY DIFFRACTION102015
2.73-2.830.32189800.327X-RAY DIFFRACTION103115
2.83-2.960.32789620.3116X-RAY DIFFRACTION101315
2.96-3.120.34959580.3173X-RAY DIFFRACTION101315
3.12-3.310.3229920.2817X-RAY DIFFRACTION105515
3.31-3.570.31119720.2655X-RAY DIFFRACTION102715
3.57-3.930.27449810.244X-RAY DIFFRACTION102915
3.93-4.490.30089940.2162X-RAY DIFFRACTION104815
4.49-5.630.305710040.2258X-RAY DIFFRACTION106115
5.63-200.277210420.2227X-RAY DIFFRACTION108915

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