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- PDB-4zyc: Discovery of dihydroisoquinolinone derivatives as novel inhibitor... -

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Entry
Database: PDB / ID: 4zyc
TitleDiscovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / PPI WITH P53 / 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-4SS / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.95 Å
AuthorsKallen, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2015
Title: Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode.
Authors: Gessier, F. / Kallen, J. / Jacoby, E. / Chene, P. / Stachyra-Valat, T. / Ruetz, S. / Jeay, S. / Holzer, P. / Masuya, K. / Furet, P.
History
DepositionMay 21, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 22, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 12, 2015Group: Database references
Revision 1.2Nov 29, 2017Group: Database references / Category: pdbx_database_related
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)35,2147
Polymers33,5163
Non-polymers1,6984
Water1,874104
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,2403
Polymers11,1721
Non-polymers1,0682
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7062
Polymers11,1721
Non-polymers5341
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,2682
Polymers11,1721
Non-polymers961
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)39.020, 49.780, 75.287
Angle α, β, γ (deg.)90.000, 92.770, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 11172.008 Da / Num. of mol.: 3
Fragment: N-TERMINAL DOMAIN, P53-BINDING DOMAIN, UNP residues 17-111
Mutation: L33E
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-4SS / (S)-2-(2-((2H-tetrazol-5-yl)methoxy)-4-methylphenyl)-1-(4-chlorophenyl)-6,7-diethoxy-1,2-dihydroisoquinolin-3(4H)-one


Mass: 534.006 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C28H28ClN5O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 104 / 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: 0 Å3/Da / Density % sol: 0 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8
Details: reservoir: 2.2M ammonium sulphate, 0.2M KNa tartrate, protein: 10mg/ml Hdm2 in 50mM TRIS pH 8.0, 200mM NaCl, 1mM TCEP, 10% glycerol, drop: 0.2ul reservoir + 0.2ul protein
PH range: 8

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 0.9794 Å
DetectorType: MARRESEARCH / Detector: CCD / Date: Nov 7, 2008
RadiationMonochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9794 Å / Relative weight: 1
ReflectionResolution: 1.95→20 Å / Num. obs: 21169 / % possible obs: 99.8 % / Redundancy: 5.3 % / Rmerge(I) obs: 0.056 / Χ2: 0.979 / Net I/av σ(I): 31.07 / Net I/σ(I): 31.07 / Num. measured all: 112750
Reflection shellResolution: 1.95→2.02 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.25 / Mean I/σ(I) obs: 4.21 / Num. unique all: 2147 / Χ2: 1.789 / Rejects: 0 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
DENZOdata reduction
SCALEPACKdata scaling
MOLREPphasing
REFMAC5.5.0063refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DIJ

4dij


Resolution: 1.95→20 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.2718 / WRfactor Rwork: 0.2326 / FOM work R set: 0.8309 / SU B: 3.718 / SU ML: 0.11 / SU R Cruickshank DPI: 0.2044 / SU Rfree: 0.1754 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.204 / ESU R Free: 0.175 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2587 1089 5.1 %RANDOM
Rwork0.2203 ---
obs0.2222 20068 99.77 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 73.82 Å2 / Biso mean: 30.121 Å2 / Biso min: 16.48 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20 Å2-0.77 Å2
2--0.37 Å20 Å2
3----1.01 Å2
Refinement stepCycle: final / Resolution: 1.95→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 119 104 2338
Biso mean--27.14 40.14 -
Num. residues----255
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0222287
X-RAY DIFFRACTIONr_angle_refined_deg1.0572.0533087
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.625252
X-RAY DIFFRACTIONr_dihedral_angle_2_deg45.84923.47892
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.45115427
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.8181512
X-RAY DIFFRACTIONr_chiral_restr0.0680.2334
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211664
LS refinement shellResolution: 1.95→2 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.268 74 -
Rwork0.214 1450 -
all-1524 -
obs--100 %

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