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- PDB-5oai: Structure of MDM2 with low molecular weight inhibitor -

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Basic information

Entry
Database: PDB / ID: 5oai
TitleStructure of MDM2 with low molecular weight inhibitor
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / p53 / MDM2 / MDMX / protein-protein interaction / cancer / inhibitor
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 / peroxisome proliferator activated receptor binding / response to iron ion / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / cellular response to alkaloid / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / 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 / protein sumoylation / ligase activity / 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 / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / RING-type E3 ubiquitin transferase / cellular response to gamma radiation / 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 / negative regulation of neuron projection development / p53 binding / 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-B5K / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2 Å
AuthorsTwarda-Clapa, A. / Neochoritis, C.G. / Grudnik, P. / Dubin, G. / Domling, A. / Holak, T.A.
CitationJournal: Febs J. / Year: 2019
Title: A fluorinated indole-based MDM2 antagonist selectively inhibits the growth of p53wtosteosarcoma cells.
Authors: Skalniak, L. / Twarda-Clapa, A. / Neochoritis, C.G. / Surmiak, E. / Machula, M. / Wisniewska, A. / Labuzek, B. / Ali, A.M. / Krzanik, S. / Dubin, G. / Groves, M. / Domling, A. / Holak, T.A.
History
DepositionJun 22, 2017Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 13, 2019Provider: repository / Type: Initial release
Revision 1.1Apr 17, 2019Group: Data collection / Database references / Category: citation / pdbx_database_proc
Item: _citation.journal_abbrev / _citation.journal_id_ISSN ..._citation.journal_abbrev / _citation.journal_id_ISSN / _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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)11,8952
Polymers11,3991
Non-polymers4961
Water73941
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area6040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)49.731, 59.216, 83.897
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222

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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 genetically manipulated source
Details: Met 17 is a translation initiating Met. / Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Chemical ChemComp-B5K / 3-[(1~{R})-2-(~{tert}-butylamino)-1-[methanoyl-[[3,4,5-tris(fluoranyl)phenyl]methyl]amino]-2-oxidanylidene-ethyl]-6-chloranyl-1~{H}-indole-2-carboxylic acid


Mass: 495.879 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H21ClF3N3O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.71 Å3/Da / Density % sol: 54.6 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 6.5 / Details: 0.1 M Bis-Tris pH 6.5, 20% (w/v) PEG 5000 MME

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Data collection

DiffractionMean temperature: 277 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Jan 20, 2017
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2→42.78 Å / Num. obs: 8652 / % possible obs: 99.24 % / Redundancy: 6.4 % / Rmerge(I) obs: 0.058 / Rpim(I) all: 0.037 / Rrim(I) all: 0.069 / Net I/σ(I): 16
Reflection shellResolution: 2→2.072 Å / Rmerge(I) obs: 0.477 / Num. unique all: 839 / Rpim(I) all: 0.299 / Rrim(I) all: 0.564 / % possible all: 98.35

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Processing

Software
NameVersionClassification
PHENIX(1.11.1_2575: ???)refinement
SCALA3.3.21data scaling
XDSdata reduction
PHASER2.5.5phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TJ2

3tj2


Resolution: 2→42.78 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 30.56 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.2273 406 4.71 %
Rwork0.2156 --
obs0.2161 8621 99.23 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2→42.78 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms792 0 34 41 867
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.003850
X-RAY DIFFRACTIONf_angle_d1.0511154
X-RAY DIFFRACTIONf_dihedral_angle_d7.839712
X-RAY DIFFRACTIONf_chiral_restr0.087128
X-RAY DIFFRACTIONf_plane_restr0.003142
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.0001-2.28950.28161430.26512652X-RAY DIFFRACTION98
2.2895-2.88440.26521390.24912710X-RAY DIFFRACTION99
2.8844-42.78970.19651240.19482853X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.331-2.56411.46732.6479-0.17322.0446-0.1684-0.1203-0.0209-0.0131-0.01040.85340.1687-0.4266-0.43980.3928-0.0388-0.04250.3195-0.01590.594550.263312.028216.974
22.2337-0.71720.95251.787-0.16151.18660.71331.2958-0.1828-1.6187-0.34090.07180.97680.4083-0.21170.80440.1027-0.08460.54270.00550.472756.70727.88364.2127
33.35190.29920.60043.27630.12853.19990.3190.3844-0.616-0.4079-0.27850.74190.1403-0.22160.04420.3208-0.0452-0.04980.3211-0.0290.467356.05791.754811.6755
41.4058-0.22950.44643.1345-1.48843.60340.10780.1359-0.1885-0.2066-0.2151-0.1140.32440.0213-0.00760.30620.036-0.00070.3281-0.02410.359567.9217-4.524917.7641
54.02030.46450.32494.70310.89051.7422-0.07190.01680.0170.1794-0.1166-0.021-0.51870.306-0.01840.30460.0304-0.03950.253-0.01230.346566.62145.218118.2647
62.1590.6768-1.28084.1109-1.04336.15120.09110.07910.1786-0.0083-0.14950.5372-0.31210.14510.04660.27630.0049-0.02630.2246-0.02810.378656.627714.507716.9595
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 17 through 31 )
2X-RAY DIFFRACTION2chain 'A' and (resid 32 through 49 )
3X-RAY DIFFRACTION3chain 'A' and (resid 50 through 63 )
4X-RAY DIFFRACTION4chain 'A' and (resid 64 through 80 )
5X-RAY DIFFRACTION5chain 'A' and (resid 81 through 95 )
6X-RAY DIFFRACTION6chain 'A' and (resid 96 through 113 )

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