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- PDB-6ggn: In vitro and in vivo characterization of a novel, highly potent p... -

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Basic information

Entry
Database: PDB / ID: 6ggn
TitleIn vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor
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 / 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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / 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 / proteolysis involved in protein catabolic process / ubiquitin binding / response to cocaine / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / establishment of protein localization / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / cellular response to gamma radiation / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / response to toxic substance / 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-EYH / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsKallen, J.
CitationJournal: Bioorg. Med. Chem. Lett. / Year: 2018
Title: In vitro and in vivo characterization of a novel, highly potent p53-MDM2 inhibitor.
Authors: Vaupel, A. / Holzer, P. / Ferretti, S. / Guagnano, V. / Kallen, J. / Mah, R. / Masuya, K. / Ruetz, S. / Rynn, C. / Schlapbach, A. / Stachyra, T. / Stutz, S. / Todorov, M. / Jeay, S. / Furet, P.
History
DepositionMay 3, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 26, 2018Provider: repository / Type: Initial release
Revision 1.1Oct 24, 2018Group: Data collection / Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Jan 17, 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)11,7443
Polymers11,1561
Non-polymers5882
Water93752
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area110 Å2
ΔGint-7 kcal/mol
Surface area5810 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.080, 56.080, 106.698
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-306-

HOH

21A-316-

HOH

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Components

#1: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / RING-type E3 ubiquitin transferase Mdm2 / p53- ...Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / RING-type E3 ubiquitin transferase 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 BL21 (bacteria)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-EYH / (4~{S})-4-(4-chloranyl-2-methyl-phenyl)-5-(5-chloranyl-2-methyl-phenyl)-2-(2,4-dimethoxypyrimidin-5-yl)-3-propan-2-yl-4~{H}-pyrrolo[3,4-d]imidazol-6-one


Mass: 552.452 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H27Cl2N5O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


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


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.17 Å3/Da / Density % sol: 43.34 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 5.5 / Details: 2.5M (NH4)2SO4, 0.1M NaCitrate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Mar 26, 2011
RadiationMonochromator: SI 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2→19.54 Å / Num. obs: 7181 / % possible obs: 99.5 % / Redundancy: 17.7 % / Biso Wilson estimate: 35.8 Å2 / Rmerge(I) obs: 0.09 / Rpim(I) all: 0.052 / Rrim(I) all: 0.093 / Net I/σ(I): 23 / Num. measured all: 127042
Reflection shellResolution: 2→2.05 Å / Redundancy: 17.5 % / Rmerge(I) obs: 0.625 / Mean I/σ(I) obs: 5.2 / Rpim(I) all: 0.284 / Rrim(I) all: 0.644 / % possible all: 98.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5LN2

5ln2


Resolution: 2→19.54 Å / Cor.coef. Fo:Fc: 0.942 / Cor.coef. Fo:Fc free: 0.949 / SU B: 4.547 / SU ML: 0.125 / SU R Cruickshank DPI: 0.2324 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.232 / ESU R Free: 0.168
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2304 359 5 %RANDOM
Rwork0.2214 ---
obs0.2218 6820 99.5 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 67.11 Å2 / Biso mean: 31.882 Å2 / Biso min: 14.28 Å2
Baniso -1Baniso -2Baniso -3
1-0.35 Å20.35 Å20 Å2
2--0.35 Å20 Å2
3----1.15 Å2
Refinement stepCycle: final / Resolution: 2→19.54 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms773 0 39 52 864
Biso mean--28.25 43.31 -
Num. residues----94
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.022848
X-RAY DIFFRACTIONr_angle_refined_deg0.9892.0511157
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.694599
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.44324.28635
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.215157
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.683154
X-RAY DIFFRACTIONr_chiral_restr0.0650.2128
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021628
LS refinement shellResolution: 2→2.051 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.257 24 -
Rwork0.295 470 -
all-494 -
obs--98.21 %

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