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- PDB-5ln2: Discovery of a novel class of highly potent inhibitors of the p53... -

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Basic information

Entry
Database: PDB / ID: 5ln2
TitleDiscovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsCELL CYCLE / 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 / 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 / response to ether / traversing start control point of mitotic cell cycle / 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 / response to iron ion / peroxisome proliferator activated receptor binding / negative regulation of protein processing / response to steroid hormone / NEDD8 ligase activity / SUMO transferase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / cellular response to alkaloid / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / ligase activity / protein sumoylation / SUMOylation of transcription factors / protein localization to nucleus / cellular response to actinomycin D / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / cellular response to gamma radiation / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of TP53 Degradation / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / protein ubiquitination / regulation of cell cycle / Ub-specific processing proteases / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / nucleolus / negative regulation of apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding
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-6ZT / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.58 Å
AuthorsKallen, J.
CitationJournal: Bioorg.Med.Chem.Lett. / Year: 2016
Title: Discovery of a novel class of highly potent inhibitors of the p53-MDM2 interaction by structure-based design starting from a conformational argument.
Authors: Furet, P. / Masuya, K. / Kallen, J. / Stachyra-Valat, T. / Ruetz, S. / Guagnano, V. / Holzer, P. / Mah, R. / Stutz, S. / Vaupel, A. / Chene, P. / Jeay, S. / Schlapbach, A.
History
DepositionAug 2, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 7, 2016Provider: repository / Type: Initial release
Revision 1.1Sep 21, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)11,8814
Polymers11,1561
Non-polymers7253
Water2,090116
1


  • Idetical with deposited unit
  • defined by software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area310 Å2
ΔGint-21 kcal/mol
Surface area5900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.540, 56.540, 103.953
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: 11156.052 Da / Num. of mol.: 1 / Fragment: N-terminal domain, p53 binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-6ZT / (4~{S})-5-[5-chloranyl-2-[2-(dimethylamino)ethoxy]phenyl]-4-(4-chloranyl-2-methyl-phenyl)-2-(2-methoxyphenyl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-c]pyrazol-6-one


Mass: 593.543 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H34Cl2N4O3
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.15 Å3/Da / Density % sol: 42.78 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5 / Details: 2.5M (NH4)2SO4, 0.1M NaCitrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Sep 14, 2010
RadiationMonochromator: SI 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.58→20 Å / Num. obs: 14090 / % possible obs: 99.8 % / Redundancy: 22.2 % / Biso Wilson estimate: 24.5 Å2 / Rmerge(I) obs: 0.045 / Net I/σ(I): 48
Reflection shellResolution: 1.58→20 Å / Redundancy: 14.9 % / Rmerge(I) obs: 0.277 / Mean I/σ(I) obs: 10.3 / % possible all: 99.1

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassification
XSCALEdata scaling
PHASERphasing
REFMAC5.7.0032refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZYF

4zyf


Resolution: 1.58→18.51 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.932 / SU B: 1.677 / SU ML: 0.061 / SU R Cruickshank DPI: 0.1097 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.11 / ESU R Free: 0.107
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2474 704 5 %RANDOM
Rwork0.2148 ---
obs0.2164 13384 99.81 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 58.74 Å2 / Biso mean: 19.35 Å2 / Biso min: 8.94 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refinement stepCycle: final / Resolution: 1.58→18.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms779 0 47 116 942
Biso mean--18.76 34.06 -
Num. residues----95
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.022867
X-RAY DIFFRACTIONr_angle_refined_deg1.0092.061184
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.4015102
X-RAY DIFFRACTIONr_dihedral_angle_2_deg45.49324.28635
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.86515160
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.633154
X-RAY DIFFRACTIONr_chiral_restr0.0710.2131
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021635
X-RAY DIFFRACTIONr_mcbond_it0.8071.614387
X-RAY DIFFRACTIONr_mcangle_it1.4292.412484
X-RAY DIFFRACTIONr_scbond_it0.9991.783479
LS refinement shellResolution: 1.58→1.621 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.31 50 -
Rwork0.243 948 -
all-998 -
obs--99.11 %

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