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- PDB-5mnj: Structure of MDM2-MDMX-UbcH5B-ubiquitin complex -

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Basic information

Entry
Database: PDB / ID: 5mnj
TitleStructure of MDM2-MDMX-UbcH5B-ubiquitin complex
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Polyubiquitin-B
  • Protein Mdm4
  • Ubiquitin-conjugating enzyme E2 D2
KeywordsLIGASE / Ubiquitin ligase
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / (E3-independent) E2 ubiquitin-conjugating enzyme / 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 ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / (E3-independent) E2 ubiquitin-conjugating enzyme / 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 / heart valve development / positive regulation of vascular associated smooth muscle cell migration / hypothalamus gonadotrophin-releasing hormone neuron development / peroxisome proliferator activated receptor binding / response to iron ion / negative regulation of protein processing / response to steroid hormone / SUMO transferase activity / NEDD8 ligase activity / female meiosis I / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / E2 ubiquitin-conjugating enzyme / fat pad development / ventricular septum development / endocardial cushion morphogenesis / female gonad development / cellular response to alkaloid / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / seminiferous tubule development / blood vessel development / regulation of protein catabolic process / male meiosis I / cardiac septum morphogenesis / ubiquitin conjugating enzyme activity / 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 / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / protein localization to nucleus / cellular response to actinomycin D / DNA damage response, signal transduction by p53 class mediator / cellular response to UV-C / protein K48-linked ubiquitination / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / regulation of proteasomal protein catabolic process / ribonucleoprotein complex binding / ubiquitin ligase complex / energy homeostasis / regulation of neuron apoptotic process / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Prevention of phagosomal-lysosomal fusion / IRAK2 mediated activation of TAK1 complex / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Constitutive Signaling by NOTCH1 HD Domain Mutants / NOTCH2 Activation and Transmission of Signal to the Nucleus / positive regulation of vascular associated smooth muscle cell proliferation / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / Regulation of FZD by ubiquitination / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / Downregulation of ERBB4 signaling / p75NTR recruits signalling complexes / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / transcription repressor complex / TRAF6-mediated induction of TAK1 complex within TLR4 complex / InlA-mediated entry of Listeria monocytogenes into host cells / Pexophagy / Regulation of innate immune responses to cytosolic DNA / NPAS4 regulates expression of target genes / VLDLR internalisation and degradation / regulation of heart rate / Downregulation of ERBB2:ERBB3 signaling / NRIF signals cell death from the nucleus
Similarity search - Function
MDM4 / 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) ...MDM4 / 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 / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme/RWD-like / Zinc/RING finger domain, C3HC4 (zinc finger) / Herpes Virus-1 / Ubiquitin conserved site / Ubiquitin domain / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin domain signature. / Ubiquitin family / Ubiquitin homologues / Ubiquitin-like domain / Ubiquitin domain profile. / Ubiquitin-like domain superfamily / Zinc finger, RING/FYVE/PHD-type / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
Protein Mdm4 / Polyubiquitin-B / Ubiquitin-conjugating enzyme E2 D2 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.16 Å
AuthorsKlejnot, M. / Huang, D.T.
Funding support United Kingdom, 2items
OrganizationGrant numberCountry
Cancer Research UK United Kingdom
European Research Council647849
CitationJournal: Nat. Struct. Mol. Biol. / Year: 2017
Title: Structural analysis of MDM2 RING separates degradation from regulation of p53 transcription activity.
Authors: Nomura, K. / Klejnot, M. / Kowalczyk, D. / Hock, A.K. / Sibbet, G.J. / Vousden, K.H. / Huang, D.T.
History
DepositionDec 13, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 31, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2017Group: Database references
Revision 1.2Jul 19, 2017Group: Database references / Category: citation
Item: _citation.country / _citation.journal_volume ..._citation.country / _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.3May 8, 2019Group: Advisory / Data collection / Derived calculations
Category: diffrn_source / pdbx_validate_close_contact ...diffrn_source / pdbx_validate_close_contact / struct_conn / struct_conn_type
Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.4Jul 10, 2019Group: Data collection / Category: diffrn_source / Item: _diffrn_source.pdbx_synchrotron_site
Revision 1.5Oct 16, 2019Group: Data collection / Category: reflns_shell
Revision 1.6Jan 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: Ubiquitin-conjugating enzyme E2 D2
B: Polyubiquitin-B
C: E3 ubiquitin-protein ligase Mdm2
D: Protein Mdm4
E: Ubiquitin-conjugating enzyme E2 D2
F: Polyubiquitin-B
G: E3 ubiquitin-protein ligase Mdm2
H: Protein Mdm4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)86,01518
Polymers85,2998
Non-polymers71510
Water1,38777
1
A: Ubiquitin-conjugating enzyme E2 D2
B: Polyubiquitin-B
C: E3 ubiquitin-protein ligase Mdm2
D: Protein Mdm4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0079
Polymers42,6504
Non-polymers3585
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
E: Ubiquitin-conjugating enzyme E2 D2
F: Polyubiquitin-B
G: E3 ubiquitin-protein ligase Mdm2
H: Protein Mdm4
hetero molecules


Theoretical massNumber of molelcules
Total (without water)43,0079
Polymers42,6504
Non-polymers3585
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)54.240, 62.760, 66.350
Angle α, β, γ (deg.)69.83, 69.22, 78.21
Int Tables number1
Space group name H-MP1

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Components

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Protein , 4 types, 8 molecules AEBFCGDH

#1: Protein Ubiquitin-conjugating enzyme E2 D2 / (E3-independent) E2 ubiquitin-conjugating enzyme D2 / E2 ubiquitin-conjugating enzyme D2 / ...(E3-independent) E2 ubiquitin-conjugating enzyme D2 / E2 ubiquitin-conjugating enzyme D2 / Ubiquitin carrier protein D2 / Ubiquitin-conjugating enzyme E2(17)KB 2 / Ubiquitin-conjugating enzyme E2-17 kDa 2 / Ubiquitin-protein ligase D2 / p53-regulated ubiquitin-conjugating enzyme 1


Mass: 16851.381 Da / Num. of mol.: 2 / Mutation: S22R, C85K
Source method: isolated from a genetically manipulated source
Details: K85 in Chains A and E form isopeptide linkage with the carbonyl carbon of G76 in Chains B and F, respectively.
Source: (gene. exp.) Homo sapiens (human) / Gene: UBE2D2, PUBC1, UBC4, UBC5B, UBCH4, UBCH5B / Production host: Escherichia coli (E. coli)
References: UniProt: P62837, E2 ubiquitin-conjugating enzyme, (E3-independent) E2 ubiquitin-conjugating enzyme
#2: Protein Polyubiquitin-B


Mass: 8922.141 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: gsggs linker at the N-terminus resulted from cloning. G76 in chain B is covalently linked to K85 side chain in Chain A.
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47
#3: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / p53-binding protein Mdm2


Mass: 9668.399 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Contains N-terminal His-tag followed by TEV protease cleavage site that was not removed during purification. MDM2 contains 428-491.
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)
#4: Protein Protein Mdm4 / Double minute 4 protein / Mdm2-like p53-binding protein / Protein Mdmx / p53-binding protein Mdm4


Mass: 7207.716 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: MDMX contains 427-490 / Source: (gene. exp.) Homo sapiens (human) / Gene: MDM4, MDMX / Production host: Escherichia coli (E. coli) / References: UniProt: O15151

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Non-polymers , 3 types, 87 molecules

#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Zn
#6: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 77 / 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: 2.31 Å3/Da / Density % sol: 46.84 %
Crystal growTemperature: 292 K / Method: vapor diffusion, hanging drop
Details: 0.1 M Tris-HCl, pH 8.5, 0.175 M Li2SO4 and 16-20 %(v/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I24 / Wavelength: 0.97879 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 21, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97879 Å / Relative weight: 1
ReflectionResolution: 2.16→50.5 Å / Num. obs: 37881 / % possible obs: 95.3 % / Redundancy: 3.2 % / Net I/σ(I): 6.8

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Processing

Software
NameVersionClassification
PHENIX1.7.1_743refinement
XDSdata reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3ZNI and 3VJF

3zni

3vjf


Resolution: 2.16→50.49 Å / SU ML: 0.59 / Cross valid method: FREE R-VALUE / σ(F): 1.96 / Phase error: 30.25
RfactorNum. reflection% reflection
Rfree0.2308 1911 5.04 %
Rwork0.1901 --
obs0.1922 37881 92.37 %
Solvent computationShrinkage radii: 0.95 Å / VDW probe radii: 1.2 Å / Bsol: 46.114 Å2 / ksol: 0.336 e/Å3
Displacement parameters
Baniso -1Baniso -2Baniso -3
1-6.2309 Å28.5766 Å29.6468 Å2
2---0.5048 Å211.81 Å2
3----5.7261 Å2
Refinement stepCycle: LAST / Resolution: 2.16→50.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms5290 0 18 77 5385
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0085456
X-RAY DIFFRACTIONf_angle_d1.2547427
X-RAY DIFFRACTIONf_dihedral_angle_d14.5052026
X-RAY DIFFRACTIONf_chiral_restr0.086857
X-RAY DIFFRACTIONf_plane_restr0.007950
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.1601-2.21410.36381160.30992367X-RAY DIFFRACTION85
2.2141-2.2740.4071390.28962378X-RAY DIFFRACTION86
2.274-2.34090.32491340.2742414X-RAY DIFFRACTION87
2.3409-2.41640.31121340.2452432X-RAY DIFFRACTION88
2.4164-2.50280.29621230.23472534X-RAY DIFFRACTION90
2.5028-2.6030.31991210.23752498X-RAY DIFFRACTION90
2.603-2.72150.29841370.2442591X-RAY DIFFRACTION92
2.7215-2.86490.29581480.22582585X-RAY DIFFRACTION93
2.8649-3.04440.2551380.2152634X-RAY DIFFRACTION95
3.0444-3.27940.24541460.19692662X-RAY DIFFRACTION96
3.2794-3.60940.25241340.1952697X-RAY DIFFRACTION97
3.6094-4.13140.21161630.16672739X-RAY DIFFRACTION98
4.1314-5.20430.17651330.14322720X-RAY DIFFRACTION98
5.2043-50.50360.17731450.17322719X-RAY DIFFRACTION98

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