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- PDB-7ai1: Crystal structure of human MDM2-G443T RING domain homodimer bound... -

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Basic information

Entry
Database: PDB / ID: 7ai1
TitleCrystal structure of human MDM2-G443T RING domain homodimer bound to UbcH5B-Ub (Crystal form 2)
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 / (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 / hypothalamus gonadotrophin-releasing hormone neuron development / peroxisome proliferator activated receptor binding / response to iron ion / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / female meiosis I / positive regulation of protein monoubiquitination / mitochondrion transport along microtubule / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / fat pad development / ventricular septum development / endocardial cushion morphogenesis / E2 ubiquitin-conjugating enzyme / female gonad development / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / seminiferous tubule development / cellular response to alkaloid / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / male meiosis I / Constitutive Signaling by AKT1 E17K in Cancer / positive regulation of intrinsic apoptotic signaling pathway by p53 class mediator / ligase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / ubiquitin conjugating enzyme activity / response to magnesium ion / protein sumoylation / SUMOylation of transcription factors / protein localization to nucleus / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / protein K48-linked ubiquitination / cellular response to actinomycin D / ribonucleoprotein complex binding / energy homeostasis / regulation of neuron apoptotic process / regulation of proteasomal protein catabolic process / 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 / Downregulation of ERBB2:ERBB3 signaling / NF-kB is activated and signals survival / NRIF signals cell death from the nucleus / regulation of heart rate / Regulation of PTEN localization
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. / 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: 2.07 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 2.0Jan 27, 2021Group: Atomic model / Database references / Category: atom_site / 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 2.1Feb 10, 2021Group: Database references / Category: citation / Item: _citation.journal_volume / _citation.title
Revision 2.2May 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)68,66414
Polymers68,2076
Non-polymers4578
Water5,008278
1
AAA: E3 ubiquitin-protein ligase Mdm2
DDD: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)16,9928
Polymers16,6602
Non-polymers3336
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)34,3948
Polymers34,1033
Non-polymers2905
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)34,2706
Polymers34,1033
Non-polymers1663
Water543
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)56.267, 80.687, 135.909
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
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, 286 molecules

#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / 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 / Ethylene glycol


Mass: 62.068 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C2H6O2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 278 / 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: 2.26 Å3/Da / Density % sol: 45.61 %
Crystal growTemperature: 292 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M HEPES, 0.2 M NH4NO3, 20 % w/v PEG Smear Broad

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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: 2.07→135.91 Å / Num. obs: 38548 / % possible obs: 100 % / Redundancy: 6.4 % / CC1/2: 0.997 / Net I/σ(I): 9
Reflection shellResolution: 2.07→2.11 Å / Num. unique obs: 1861 / CC1/2: 0.584

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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

Resolution: 2.07→69.478 Å / Cor.coef. Fo:Fc: 0.947 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.241 / WRfactor Rwork: 0.191 / SU B: 6.44 / SU ML: 0.165 / Average fsc free: 0.8728 / Average fsc work: 0.8939 / Cross valid method: FREE R-VALUE / ESU R: 0.234 / ESU R Free: 0.203
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.266 1887 4.925 %
Rwork0.2121 36425 -
all0.215 --
obs-38312 99.517 %
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: 32.5 Å2
Baniso -1Baniso -2Baniso -3
1--1.177 Å2-0 Å2-0 Å2
2---0.078 Å20 Å2
3---1.255 Å2
Refinement stepCycle: LAST / Resolution: 2.07→69.478 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4458 0 14 278 4750
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0070.0134587
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174346
X-RAY DIFFRACTIONr_angle_refined_deg1.4341.666225
X-RAY DIFFRACTIONr_angle_other_deg1.261.57710138
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.4815567
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.60122.347213
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.64815802
X-RAY DIFFRACTIONr_dihedral_angle_4_deg17.0851527
X-RAY DIFFRACTIONr_chiral_restr0.0680.2626
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.025020
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02877
X-RAY DIFFRACTIONr_nbd_refined0.1910.2880
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1860.24043
X-RAY DIFFRACTIONr_nbtor_refined0.1580.22175
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.090.21858
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1660.2270
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_other0.0160.21
X-RAY DIFFRACTIONr_metal_ion_refined0.0980.22
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1990.210
X-RAY DIFFRACTIONr_nbd_other0.1680.239
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1860.214
X-RAY DIFFRACTIONr_mcbond_it2.5743.3642274
X-RAY DIFFRACTIONr_mcbond_other2.5743.3632272
X-RAY DIFFRACTIONr_mcangle_it3.7945.0352833
X-RAY DIFFRACTIONr_mcangle_other3.7945.0352833
X-RAY DIFFRACTIONr_scbond_it3.0223.692313
X-RAY DIFFRACTIONr_scbond_other3.0213.692314
X-RAY DIFFRACTIONr_scangle_it4.6825.4053390
X-RAY DIFFRACTIONr_scangle_other4.6815.4053391
X-RAY DIFFRACTIONr_lrange_it6.6140.2855036
X-RAY DIFFRACTIONr_lrange_other6.60940.2875037
X-RAY DIFFRACTIONr_ncsr_local_group_10.1180.051645
X-RAY DIFFRACTIONr_ncsr_local_group_20.1040.054508
X-RAY DIFFRACTIONr_ncsr_local_group_30.0760.052254
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.07-2.1240.3581290.3282614X-RAY DIFFRACTION98.4919
2.124-2.1820.3371610.322561X-RAY DIFFRACTION99.3068
2.182-2.2450.3551570.2942486X-RAY DIFFRACTION99.4731
2.245-2.3140.3021340.2652419X-RAY DIFFRACTION99.4546
2.314-2.390.3071070.2622400X-RAY DIFFRACTION99.3658
2.39-2.4740.3161020.2552305X-RAY DIFFRACTION99.5039
2.474-2.5670.3141160.2472242X-RAY DIFFRACTION99.7462
2.567-2.6720.3151100.2372154X-RAY DIFFRACTION99.4728
2.672-2.7910.294950.2322052X-RAY DIFFRACTION99.4903
2.791-2.9270.282870.2181988X-RAY DIFFRACTION99.7596
2.927-3.0850.2591020.2071897X-RAY DIFFRACTION99.7008
3.085-3.2720.316680.2041802X-RAY DIFFRACTION99.7866
3.272-3.4980.2491020.2031681X-RAY DIFFRACTION99.832
3.498-3.7780.239690.21588X-RAY DIFFRACTION99.8193
3.778-4.1380.226730.1581444X-RAY DIFFRACTION99.8026
4.138-4.6260.186780.1461327X-RAY DIFFRACTION99.6454
4.626-5.3410.228570.1611185X-RAY DIFFRACTION99.8392
5.341-6.5390.288640.201997X-RAY DIFFRACTION99.6244
6.539-9.2370.194460.171811X-RAY DIFFRACTION99.6512
9.237-69.4780.2300.162472X-RAY DIFFRACTION99.6032

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