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- PDB-2axi: HDM2 in complex with a beta-hairpin -

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Basic information

Entry
Database: PDB / ID: 2axi
TitleHDM2 in complex with a beta-hairpin
Components
  • Ubiquitin-protein ligase E3 Mdm2
  • cyclic 8-mer peptide
KeywordsLIGASE/LIGASE INHIBITOR / P53 / DRUG DESIGN / PROTEIN-PROTEIN INTERACTIONS / LIGASE / LIGASE-LIGASE INHIBITOR complex
Function / homology
Function and homology information


: / cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / 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 / 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 / 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 / ventricular septum development / endocardial cushion morphogenesis / 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 / Constitutive Signaling by AKT1 E17K in Cancer / ligase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / 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 / cellular response to actinomycin D / ribonucleoprotein complex binding / positive regulation of vascular associated smooth muscle cell proliferation / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / proteolysis involved in protein catabolic process / 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 / establishment of protein localization / Signaling by ALK fusions and activated point mutants / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / regulation of cell cycle / Ub-specific processing proteases / protein ubiquitination / 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 / enzyme binding / negative regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion 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
cyclo(L-alpha-aspartyl-L-tryptophyl-L-alpha-glutamyl-L-phenylalanyl-D-prolyl-L-prolyl-L-phenylalanyl-L-alpha-glutamyl-6 -chloro-L-tryptophyl-L-leucyl) / E3 ubiquitin-protein ligase Mdm2 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsMittl, P.R.E. / Fasan, R. / Robinson, J. / Gruetter, M.G.
CitationJournal: Chembiochem / Year: 2006
Title: Structure-Activity Studies in a Family of beta-Hairpin Protein Epitope Mimetic Inhibitors of the p53-HDM2 Protein-Protein Interaction.
Authors: Fasan, R. / Dias, R.L. / Moehle, K. / Zerbe, O. / Obrecht, D. / Mittl, P.R. / Robinson, J.A.
History
DepositionSep 5, 2005Deposition site: RCSB / Processing site: RCSB
Revision 1.0Mar 21, 2006Provider: repository / Type: Initial release
Revision 1.1May 1, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Atomic model / Database references ...Atomic model / Database references / Derived calculations / Non-polymer description / Structure summary / Version format compliance
Revision 1.3Dec 12, 2012Group: Other
Revision 1.4Oct 11, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.5Aug 23, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)15,1665
Polymers14,7642
Non-polymers4013
Water1,72996
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1500 Å2
ΔGint-27 kcal/mol
Surface area6450 Å2
MethodPISA
2
A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules

A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,33110
Polymers29,5284
Non-polymers8036
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_655-x+1,y,-z+1/21
Buried area3960 Å2
ΔGint-105 kcal/mol
Surface area12390 Å2
MethodPISA
3
A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules

A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,33110
Polymers29,5284
Non-polymers8036
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area5100 Å2
ΔGint-59 kcal/mol
Surface area10820 Å2
MethodPISA
4
A: Ubiquitin-protein ligase E3 Mdm2
hetero molecules

A: Ubiquitin-protein ligase E3 Mdm2
hetero molecules

B: cyclic 8-mer peptide

B: cyclic 8-mer peptide


Theoretical massNumber of molelcules
Total (without water)30,33110
Polymers29,5284
Non-polymers8036
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_655-x+1,y,-z+1/21
crystal symmetry operation2_655-x+1,-y,z+1/21
crystal symmetry operation4_555x,-y,-z1
Buried area2450 Å2
ΔGint-66 kcal/mol
Surface area13910 Å2
MethodPISA
5
A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules

A: Ubiquitin-protein ligase E3 Mdm2
B: cyclic 8-mer peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)30,33110
Polymers29,5284
Non-polymers8036
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_554-x,y,-z-1/21
Buried area3240 Å2
ΔGint-68 kcal/mol
Surface area13110 Å2
MethodPISA
Unit cell
Length a, b, c (Å)45.180, 77.749, 61.257
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-302-

SO4

21A-352-

HOH

31A-380-

HOH

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Components

#1: Protein Ubiquitin-protein ligase E3 Mdm2 / p53-binding protein Mdm2 / Oncoprotein Mdm2 / Double minute 2 protein / Hdm2


Mass: 13364.231 Da / Num. of mol.: 1 / Fragment: HDM2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pET14b / Production host: Escherichia coli (E. coli) / Strain (production host): BL21(DE3)pLysS
References: UniProt: Q9UMT8, UniProt: Q00987*PLUS, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide cyclic 8-mer peptide


Type: Peptide-like / Class: Inhibitor / Mass: 1399.930 Da / Num. of mol.: 1 / Source method: obtained synthetically / Details: The peptide was synthesized.
References: cyclo(L-alpha-aspartyl-L-tryptophyl-L-alpha-glutamyl-L-phenylalanyl-D-prolyl-L-prolyl-L-phenylalanyl-L-alpha-glutamyl-6 -chloro-L-tryptophyl-L-leucyl)
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-MPO / 3[N-MORPHOLINO]PROPANE SULFONIC ACID / MOPS


Mass: 209.263 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H15NO4S / Comment: pH buffer*YM
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 96 / 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: 1.82115 Å3/Da / Density % sol: 32.460266 %
Description: Data was collected in-house and at the synchrotron
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.5
Details: MES, ammonium sulfate, pH 5.5, VAPOR DIFFUSION, HANGING DROP, temperature 293K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: ENRAF-NONIUS FR571 / Wavelength: 1.54 Å
DetectorType: MARRESEARCH / Detector: IMAGE PLATE / Date: Oct 1, 2003 / Details: Osmic Mirrors
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54 Å / Relative weight: 1
ReflectionResolution: 1.4→50 Å / Num. obs: 21288 / % possible obs: 98.4 % / Observed criterion σ(I): 0 / Redundancy: 4.18 % / Rmerge(I) obs: 0.09 / Net I/σ(I): 15.19
Reflection shellResolution: 1.4→1.41 Å / Redundancy: 3.9 % / Rmerge(I) obs: 0.48 / Mean I/σ(I) obs: 2.91 / % possible all: 90.8

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Processing

Software
NameVersionClassificationNB
SHELXrefinement
PDB_EXTRACT1.7data extraction
XDSdata reduction
XDSdata scaling
AMoREphasing
SHELXLrefinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YCR

1ycr


Resolution: 1.4→10 Å / σ(F): 4 / Stereochemistry target values: ENGH & HUBER
RfactorNum. reflectionSelection details
Rfree0.2336 2223 RANDOM
obs0.149 --
all-21512 -
Refinement stepCycle: LAST / Resolution: 1.4→10 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms864 0 23 96 983

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