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- PDB-8aeu: Structure of hMDM2 in complex with Nutlin-3a-aa -

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Basic information

Entry
Database: PDB / ID: 8aeu
TitleStructure of hMDM2 in complex with Nutlin-3a-aa
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / Biological activity / drug design / inhibitors / protein-protein interactions
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 / protein autoubiquitination / cellular response to estrogen stimulus / 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
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. ...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
Similarity search - Domain/homology
BETA-MERCAPTOETHANOL / Chem-M0L / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsLabuzek, B. / Golik, P. / Magiera-Mularz, K. / Berg, T.
Funding support Poland, 1items
OrganizationGrant numberCountry
Polish National Science Centre2014/12/W/NZ1/00457 Poland
CitationJournal: Chembiochem / Year: 2023
Title: Nutlin-3a-aa: Improving the Bioactivity of a p53/MDM2 Interaction Inhibitor by Introducing a Solvent-Exposed Methylene Group.
Authors: Nietzold, F. / Rubner, S. / Labuzek, B. / Golik, P. / Surmiak, E. / Del Corte, X. / Kitel, R. / Protzel, C. / Reppich-Sacher, R. / Stichel, J. / Magiera-Mularz, K. / Holak, T.A. / Berg, T.
History
DepositionJul 13, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 18, 2023Provider: repository / Type: Initial release
Revision 1.1Mar 1, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Mar 22, 2023Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.3Mar 29, 2023Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.4Feb 7, 2024Group: 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: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,0713
Polymers11,3991
Non-polymers6722
Water21612
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules

A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,1426
Polymers22,7992
Non-polymers1,3434
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation8_665-y+1,-x+1,-z+1/21
Buried area4860 Å2
ΔGint-41 kcal/mol
Surface area11120 Å2
MethodPISA
Unit cell
Length a, b, c (Å)56.233, 56.233, 75.376
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number96
Space group name H-MP43212

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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: 11399.375 Da / Num. of mol.: 1 / Source method: isolated from a natural source / Source: (natural) Homo sapiens (human)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-BME / BETA-MERCAPTOETHANOL / 2-Mercaptoethanol


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS
#3: Chemical ChemComp-M0L / 4-[[(4~{S},5~{R})-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxy-phenyl)-4,5-dihydroimidazol-1-yl]carbonyl]-3-methylidene-piperazin-2-one / Nutlin-3a analogue / 4-[[(4S,5R)-4,5-bis(4-chlorophenyl)-2-(4-methoxy-2-propan-2-yloxy-phenyl)-4,5-dihydroimidazol-1-yl]carbonyl]-3-methylidene-piperazin-2-one


Mass: 593.500 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C31H30Cl2N4O4 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 12 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.61 Å3/Da / Density % sol: 52.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.01 M magnesium chloride hexahydrate, 0.05 M Tris hydrochloride pH 7.6, 1.6 M ammonium sulfate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jul 11, 2020
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2→45.07 Å / Num. obs: 8645 / % possible obs: 100 % / Redundancy: 24.7 % / CC1/2: 1 / Rmerge(I) obs: 0.048 / Net I/σ(I): 33.6
Reflection shellResolution: 2→2.05 Å / Num. unique obs: 6799 / CC1/2: 0.805

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Processing

Software
NameVersionClassification
PHENIX1.15.2refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZFI

4zfi


Resolution: 2→45.07 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.959 / SU B: 8.544 / SU ML: 0.122 / Cross valid method: THROUGHOUT / ESU R: 0.166 / ESU R Free: 0.157 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2404 820 9.5 %RANDOM
Rwork0.1973 ---
obs0.2012 617 99.99 %-
Solvent computationIon probe radii: 1 Å / Shrinkage radii: 1 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 104.36 Å2 / Biso mean: 58.3712 Å2 / Biso min: 30 Å2
Baniso -1Baniso -2Baniso -3
1-1.33 Å2-0 Å2-0 Å2
2--1.33 Å2-0 Å2
3----2.67 Å2
Refinement stepCycle: final / Resolution: 2→45.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms720 0 45 12 777
Biso mean--54.51 58.92 -
Num. residues----87
LS refinement shellResolution: 2→2.052 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.363 60 -
Rwork0.274 554 -
all-614 -
obs--100 %
Refinement TLS params.Method: refined / Origin x: 29.008 Å / Origin y: 14.227 Å / Origin z: 18.249 Å
111213212223313233
T0.0378 Å20.0255 Å20.0219 Å2-0.0308 Å20.0107 Å2--0.0526 Å2
L3.8483 °22.404 °2-0.749 °2-2.2426 °2-0.8578 °2--1.3335 °2
S-0.0331 Å °-0.049 Å °0.1029 Å °-0.0364 Å °0.0267 Å °0.1369 Å °-0.0736 Å °-0.1569 Å °0.0063 Å °
Refinement TLS groupSelection details: { A|all }

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