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- PDB-6sqo: Crystal structure of human MDM2 RING domain homodimer bound to Ub... -

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Basic information

Entry
Database: PDB / ID: 6sqo
TitleCrystal structure of human MDM2 RING domain homodimer bound to UbcH5B-Ub
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Ubiquitin-40S ribosomal protein S27a
  • Ubiquitin-conjugating enzyme E2 D2
KeywordsLIGASE / Ubiquitin ligase / E3 / MDM2 / MDMX / E2 / phosphorylation / p53
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 / traversing start control point of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / traversing start control point of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / Formation of the ternary complex, and subsequently, the 43S complex / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / Ribosomal scanning and start codon recognition / ventricular septum development / endocardial cushion morphogenesis / Translation initiation complex formation / E2 ubiquitin-conjugating enzyme / 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 / SARS-CoV-1 modulates host translation machinery / Constitutive Signaling by AKT1 E17K in Cancer / Peptide chain elongation / Selenocysteine synthesis / ligase activity / Formation of a pool of free 40S subunits / negative regulation of DNA damage response, signal transduction by p53 class mediator / ubiquitin conjugating enzyme activity / Eukaryotic Translation Termination / response to magnesium ion / Response of EIF2AK4 (GCN2) to amino acid deficiency / protein sumoylation / SUMOylation of transcription factors / SRP-dependent cotranslational protein targeting to membrane / Viral mRNA Translation / protein localization to nucleus / Nonsense Mediated Decay (NMD) independent of the Exon Junction Complex (EJC) / GTP hydrolysis and joining of the 60S ribosomal subunit / L13a-mediated translational silencing of Ceruloplasmin expression / cellular response to UV-C / Major pathway of rRNA processing in the nucleolus and cytosol / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / Nonsense Mediated Decay (NMD) enhanced by the Exon Junction Complex (EJC) / protein K48-linked ubiquitination / cellular response to actinomycin D / ribonucleoprotein complex binding / cytosolic ribosome / ubiquitin ligase complex / 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 / positive regulation of vascular associated smooth muscle cell proliferation / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Membrane binding and targetting of GAG proteins / Endosomal Sorting Complex Required For Transport (ESCRT) / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / Negative regulation of FLT3 / Constitutive Signaling by NOTCH1 HD Domain Mutants / Regulation of FZD by ubiquitination / TICAM1,TRAF6-dependent induction of TAK1 complex / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / p75NTR recruits signalling complexes / Downregulation of ERBB4 signaling / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / APC-Cdc20 mediated degradation of Nek2A / PINK1-PRKN Mediated Mitophagy / NPAS4 regulates expression of target genes / TRAF6-mediated induction of TAK1 complex within TLR4 complex / Pexophagy / Regulation of innate immune responses to cytosolic DNA / transcription repressor complex / VLDLR internalisation and degradation / InlA-mediated entry of Listeria monocytogenes into host cells
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 / 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. / Zinc/RING finger domain, C3HC4 (zinc finger) / Herpes Virus-1 / Ubiquitin-conjugating enzyme/RWD-like / S27a-like superfamily / Ribosomal protein S27a / Ribosomal protein S27a / Ribosomal protein S27a / Zinc finger RING-type profile. / Zinc finger, RING-type / Ubiquitin domain signature. / Ubiquitin conserved site / Ubiquitin domain / Ubiquitin family / Ubiquitin homologues / Ubiquitin domain profile. / Ubiquitin-like domain / Zinc-binding ribosomal protein / Zinc finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily / 2-Layer Sandwich / Alpha Beta
Similarity search - Domain/homology
NITRATE ION / Ubiquitin-40S ribosomal protein S27a / Ubiquitin-conjugating enzyme E2 D2 / Ubiquitin-ribosomal protein eS31 fusion protein / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.41 Å
AuthorsMagnussen, H.M. / Ahmed, S.F. / Huang, D.T.
Funding support United Kingdom, Belgium, 2items
OrganizationGrant numberCountry
Cancer Research UKA23278 United Kingdom
European Research Council647849 Belgium
CitationJournal: Nat Commun / Year: 2020
Title: Structural basis for DNA damage-induced phosphoregulation of MDM2 RING domain.
Authors: Magnussen, H.M. / Ahmed, S.F. / Sibbet, G.J. / Hristova, V.A. / Nomura, K. / Hock, A.K. / Archibald, L.J. / Jamieson, A.G. / Fushman, D. / Vousden, K.H. / Weissman, A.M. / Huang, D.T.
History
DepositionSep 4, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 6, 2020Provider: repository / Type: Initial release
Revision 1.1May 13, 2020Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Jan 24, 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
B: Ubiquitin-conjugating enzyme E2 D2
C: Ubiquitin-40S ribosomal protein S27a
D: E3 ubiquitin-protein ligase Mdm2
E: Ubiquitin-conjugating enzyme E2 D2
F: Ubiquitin-40S ribosomal protein S27a
hetero molecules


Theoretical massNumber of molelcules
Total (without water)65,13716
Polymers64,6096
Non-polymers52710
Water9,836546
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance, Activity assays validated this assembly
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area10850 Å2
ΔGint-90 kcal/mol
Surface area24830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)129.709, 129.709, 70.537
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

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Protein , 3 types, 6 molecules ADBECF

#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: 6920.525 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: Construct contains MDM2 residues 419-491. Residues 419-427 are absent due to lack of electron density. GS at the N-terminus resulted from cloning.
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: 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: 16720.186 Da / Num. of mol.: 2 / Mutation: S22R, C85K
Source method: isolated from a genetically manipulated source
Details: K85 sidechains from Chains B and E form an isopeptide bond with the C-terminus of G76 in Chains C 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
#3: Protein Ubiquitin-40S ribosomal protein S27a


Mass: 8663.908 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 CHAINS C and F ARE COVALENTLY LINKED TO K85 SIDE CHAIN IN CHAINS B AND E, RESPECTIVELY.
Source: (gene. exp.) Homo sapiens (human) / Gene: RPS27A / Production host: Escherichia coli (E. coli) / References: UniProt: J3QTR3, UniProt: P62979*PLUS

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Non-polymers , 4 types, 556 molecules

#4: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#5: Chemical
ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-NO3 / NITRATE ION / Nitrate


Mass: 62.005 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: NO3
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 546 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestN

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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: 2.65 Å3/Da / Density % sol: 53.61 %
Crystal growTemperature: 292 K / Method: vapor diffusion
Details: 0.1 M SPG, pH 7.0, 10% (w/v) PEG Smear Broad, 0.15 M NH4NO3

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.916 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: May 6, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.916 Å / Relative weight: 1
ReflectionResolution: 1.41→112 Å / Num. obs: 129794 / % possible obs: 100 % / Redundancy: 8.9 % / CC1/2: 1 / Rmerge(I) obs: 0.047 / Net I/σ(I): 19.2
Reflection shellResolution: 1.41→1.43 Å / Num. unique obs: 6423 / CC1/2: 0.542

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Processing

Software
NameVersionClassification
PHENIX(1.10_2142: ???)refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5MNJ

5mnj


Resolution: 1.41→112 Å / Cross valid method: FREE R-VALUE
RfactorNum. reflection% reflection
Rfree0.173 --
Rwork0.139 --
obs-129794 100 %
Refinement stepCycle: LAST / Resolution: 1.41→112 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4482 0 16 546 5044

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