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- PDB-7ai0: Crystal structure of human MDM2-G443T RING domain homodimer bound... -

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Basic information

Entry
Database: PDB / ID: 7ai0
TitleCrystal structure of human MDM2-G443T RING domain homodimer bound to UbcH5B-Ub (Crystal form 1)
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Polyubiquitin-B
  • Ubiquitin-conjugating enzyme E2 D2
KeywordsLIGASE / Ubiquitin ligase / RING E3
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 / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / (E3-independent) E2 ubiquitin-conjugating enzyme / Trafficking of AMPA receptors ...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 / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / (E3-independent) E2 ubiquitin-conjugating enzyme / Trafficking of AMPA receptors / receptor serine/threonine kinase binding / peroxisome proliferator activated receptor binding / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / hypothalamus gonadotrophin-releasing hormone neuron development / SUMO transferase activity / response to steroid hormone / response to iron ion / atrioventricular valve morphogenesis / AKT phosphorylates targets in the cytosol / female meiosis I / NEDD8 ligase activity / positive regulation of protein monoubiquitination / fat pad development / cellular response to peptide hormone stimulus / mitochondrion transport along microtubule / endocardial cushion morphogenesis / ventricular septum development / E2 ubiquitin-conjugating enzyme / positive regulation of muscle cell differentiation / cardiac septum morphogenesis / female gonad development / regulation of postsynaptic neurotransmitter receptor internalization / SUMOylation of ubiquitinylation proteins / seminiferous tubule development / cellular response to alkaloid / blood vessel development / cellular response to antibiotic / Constitutive Signaling by AKT1 E17K in Cancer / ligase activity / regulation of protein catabolic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / negative regulation of signal transduction by p53 class mediator / SUMOylation of transcription factors / ubiquitin conjugating enzyme activity / male meiosis I / cellular response to UV-C / response to magnesium ion / protein sumoylation / cellular response to estrogen stimulus / blood vessel remodeling / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / protein K48-linked ubiquitination / energy homeostasis / positive regulation of vascular associated smooth muscle cell proliferation / neuron projection morphogenesis / sperm end piece / NPAS4 regulates expression of target genes / regulation of proteasomal protein catabolic process / transcription repressor complex / Maturation of protein E / Maturation of protein E / ER Quality Control Compartment (ERQC) / Myoclonic epilepsy of Lafora / FLT3 signaling by CBL mutants / Constitutive Signaling by NOTCH1 HD Domain Mutants / IRAK2 mediated activation of TAK1 complex / Prevention of phagosomal-lysosomal fusion / Alpha-protein kinase 1 signaling pathway / Glycogen synthesis / IRAK1 recruits IKK complex / IRAK1 recruits IKK complex upon TLR7/8 or 9 stimulation / Endosomal Sorting Complex Required For Transport (ESCRT) / Membrane binding and targetting of GAG proteins / Negative regulation of FLT3 / Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7 / PTK6 Regulates RTKs and Their Effectors AKT1 and DOK1 / positive regulation of mitotic cell cycle / Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation / IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation / NOTCH2 Activation and Transmission of Signal to the Nucleus / TICAM1,TRAF6-dependent induction of TAK1 complex / TICAM1-dependent activation of IRF3/IRF7 / APC/C:Cdc20 mediated degradation of Cyclin B / regulation of heart rate / Regulation of FZD by ubiquitination / Downregulation of ERBB4 signaling / APC-Cdc20 mediated degradation of Nek2A / : / p75NTR recruits signalling complexes / sperm principal piece / InlA-mediated entry of Listeria monocytogenes into host cells / TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling / Regulation of pyruvate metabolism / NF-kB is activated and signals survival / TRAF6-mediated induction of TAK1 complex within TLR4 complex
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 superfamily / Zinc finger RanBP2-type signature. / Zinc finger, RanBP2-type / Ubiquitin-conjugating enzyme, active site / Ubiquitin-conjugating (UBC) active site signature. / Ubiquitin-conjugating enzyme E2 / Ubiquitin-conjugating enzyme / Ubiquitin-conjugating (UBC) core domain profile. / Ubiquitin-conjugating enzyme E2, catalytic domain homologues / Ubiquitin-conjugating enzyme/RWD-like / 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 finger, RING/FYVE/PHD-type / Ubiquitin-like domain superfamily
Similarity search - Domain/homology
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: 1.559 Å
AuthorsMagnussen, H.M. / Huang, D.T.
Funding support United Kingdom, 3items
OrganizationGrant numberCountry
Cancer Research UKA17196 United Kingdom
Cancer Research UKA29256 United Kingdom
European Research Council (ERC)647849 United Kingdom
CitationJournal: J.Mol.Biol. / Year: 2021
Title: Identification of a Catalytic Active but Non-Aggregating MDM2 RING Domain Variant.
Authors: Magnussen, H.M. / Huang, D.T.
History
DepositionSep 25, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jan 20, 2021Provider: repository / Type: Initial release
Revision 1.1Jan 27, 2021Group: Database references / Category: citation
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_PubMed / _citation.title
Revision 1.2Feb 10, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 1.3May 1, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: atom_type / chem_comp_atom ...atom_type / chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z ..._atom_type.pdbx_N_electrons / _atom_type.pdbx_scat_Z / _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
AAA: E3 ubiquitin-protein ligase Mdm2
BBB: Ubiquitin-conjugating enzyme E2 D2
CCC: Polyubiquitin-B
DDD: E3 ubiquitin-protein ligase Mdm2
EEE: Ubiquitin-conjugating enzyme E2 D2
FFF: Polyubiquitin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)68,89419
Polymers68,2076
Non-polymers68713
Water11,926662
1
AAA: E3 ubiquitin-protein ligase Mdm2
DDD: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)17,0289
Polymers16,6602
Non-polymers3687
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
AAA: E3 ubiquitin-protein ligase Mdm2
BBB: Ubiquitin-conjugating enzyme E2 D2
CCC: Polyubiquitin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,50011
Polymers34,1033
Non-polymers3978
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
DDD: E3 ubiquitin-protein ligase Mdm2
EEE: Ubiquitin-conjugating enzyme E2 D2
FFF: Polyubiquitin-B
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,3948
Polymers34,1033
Non-polymers2905
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)129.531, 129.531, 70.751
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11Chains A D
22Chains B E
33Chains C F

NCS ensembles :
ID
1
2
3

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Components

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Protein , 3 types, 6 molecules AAADDDBBBEEECCCFFF

#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: 8329.913 Da / Num. of mol.: 2 / Mutation: G443T
Source method: isolated from a genetically manipulated source
Details: G417, S418: Expression tag / 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: 16851.381 Da / Num. of mol.: 2 / Mutation: S22R, C85K
Source method: isolated from a genetically manipulated source
Details: C85K is covalently linked to G76 (Molecule 3). / 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 Polyubiquitin-B


Mass: 8922.141 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: G-4,S-3,G-2,G-1,S0: Expression tag G76 is covalently linked to C85K (Molecule 2).
Source: (gene. exp.) Homo sapiens (human) / Gene: UBB / Production host: Escherichia coli (E. coli) / References: UniProt: P0CG47

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Non-polymers , 4 types, 675 molecules

#4: Chemical
ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-ZN / ZINC ION


Mass: 65.409 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Zn
#6: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: isolated from a natural source / Formula: C2H6O2
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 662 / 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: 53.56 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.1 M Tris, 0.075 M NaOAc, 0.1 M NaCl, 15 % w/v PEG Smear Medium

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04-1 / Wavelength: 0.91587 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Mar 9, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91587 Å / Relative weight: 1
ReflectionResolution: 1.559→70.75 Å / Num. obs: 95993 / % possible obs: 100 % / Redundancy: 17.3 % / CC1/2: 0.999 / Net I/σ(I): 13.8
Reflection shellResolution: 1.56→1.59 Å / Num. unique obs: 4693 / CC1/2: 0.518

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Processing

Software
NameVersionClassification
REFMAC5.8.0253refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: MDM2-E2-Ub complex

Resolution: 1.559→70.75 Å / Cor.coef. Fo:Fc: 0.977 / Cor.coef. Fo:Fc free: 0.963 / SU B: 3.621 / SU ML: 0.055 / Cross valid method: FREE R-VALUE / ESU R: 0.074 / ESU R Free: 0.071
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.1848 4694 4.89 %
Rwork0.1335 91299 -
all0.136 --
obs-95993 99.803 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 20.479 Å2
Baniso -1Baniso -2Baniso -3
1-0.232 Å20.116 Å20 Å2
2--0.232 Å2-0 Å2
3----0.752 Å2
Refinement stepCycle: LAST / Resolution: 1.559→70.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4513 0 25 662 5200
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.0134756
X-RAY DIFFRACTIONr_bond_other_d0.0170.0174537
X-RAY DIFFRACTIONr_angle_refined_deg1.7731.6616465
X-RAY DIFFRACTIONr_angle_other_deg1.6921.57910590
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.6555594
X-RAY DIFFRACTIONr_dihedral_angle_2_deg28.61421.631233
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.74315851
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.2351534
X-RAY DIFFRACTIONr_chiral_restr0.0980.2642
X-RAY DIFFRACTIONr_gen_planes_refined0.0110.025250
X-RAY DIFFRACTIONr_gen_planes_other0.0120.02940
X-RAY DIFFRACTIONr_nbd_refined0.2330.2898
X-RAY DIFFRACTIONr_symmetry_nbd_other0.2110.24286
X-RAY DIFFRACTIONr_nbtor_refined0.1710.22314
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0780.22078
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1730.2442
X-RAY DIFFRACTIONr_metal_ion_refined0.0240.23
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.20.215
X-RAY DIFFRACTIONr_nbd_other0.2230.255
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1680.232
X-RAY DIFFRACTIONr_mcbond_it2.9881.7442328
X-RAY DIFFRACTIONr_mcbond_other2.9891.7442326
X-RAY DIFFRACTIONr_mcangle_it3.6152.6322917
X-RAY DIFFRACTIONr_mcangle_other3.6152.6322917
X-RAY DIFFRACTIONr_scbond_it4.6262.2092428
X-RAY DIFFRACTIONr_scbond_other4.6272.212429
X-RAY DIFFRACTIONr_scangle_it5.2663.1263541
X-RAY DIFFRACTIONr_scangle_other5.2653.1263542
X-RAY DIFFRACTIONr_lrange_it5.47622.965464
X-RAY DIFFRACTIONr_lrange_other5.47822.965464
X-RAY DIFFRACTIONr_rigid_bond_restr7.87739293
X-RAY DIFFRACTIONr_ncsr_local_group_10.0780.051788
X-RAY DIFFRACTIONr_ncsr_local_group_20.120.054736
X-RAY DIFFRACTIONr_ncsr_local_group_30.0810.052248
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.559-1.60.323460.2576624X-RAY DIFFRACTION98.3352
1.6-1.6440.3053300.2486544X-RAY DIFFRACTION99.7388
1.644-1.6910.2793060.216397X-RAY DIFFRACTION99.851
1.691-1.7430.2593400.1766175X-RAY DIFFRACTION99.8927
1.743-1.8010.2412980.1546028X-RAY DIFFRACTION99.9368
1.801-1.8640.2182550.1355854X-RAY DIFFRACTION99.8855
1.864-1.9340.2052900.1295608X-RAY DIFFRACTION99.9492
1.934-2.0130.1822910.1185371X-RAY DIFFRACTION99.947
2.013-2.1020.1692680.1095190X-RAY DIFFRACTION99.9268
2.102-2.2050.1792900.1044956X-RAY DIFFRACTION99.9428
2.205-2.3240.1552400.0984700X-RAY DIFFRACTION99.9595
2.324-2.4650.1772340.0994480X-RAY DIFFRACTION99.9364
2.465-2.6350.1611830.0994243X-RAY DIFFRACTION99.9548
2.635-2.8460.171730.1063936X-RAY DIFFRACTION100
2.846-3.1170.1712160.1233581X-RAY DIFFRACTION100
3.117-3.4840.1821820.1363261X-RAY DIFFRACTION100
3.484-4.0210.1371610.1262891X-RAY DIFFRACTION100
4.021-4.9210.1261170.1092474X-RAY DIFFRACTION99.9614
4.921-6.9420.1771090.1821901X-RAY DIFFRACTION99.851
6.942-70.750.214650.1851085X-RAY DIFFRACTION100

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