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- PDB-5xxk: Structure-activity studies of Mdm2/Mdm4-binding stapled peptides ... -

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Basic information

Entry
Database: PDB / ID: 5xxk
TitleStructure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2
KeywordsONCOPROTEIN/INHIBITOR / E3 ubiqutin ligase / ONCOPROTEIN / ONCOPROTEIN-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 / response to ether / 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 ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / response to ether / 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 / positive regulation of vascular associated smooth muscle cell migration / peroxisome proliferator activated receptor binding / SUMO transferase activity / negative regulation of protein processing / response to iron ion / response to steroid hormone / NEDD8 ligase activity / cellular response to peptide hormone stimulus / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of protein catabolic process / blood vessel development / cardiac septum morphogenesis / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / protein sumoylation / 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 / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / proteolysis involved in protein catabolic process / ubiquitin binding / response to cocaine / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / establishment of protein localization / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / cellular response to gamma radiation / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / response to toxic substance / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / ubiquitin protein ligase activity / p53 binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / negative regulation of neuron projection development / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / proteasome-mediated ubiquitin-dependent protein catabolic process / 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 / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm
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
E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
Phage display vector pTDisp (others)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.66 Å
AuthorsBrown, C.J.
Funding support Singapore, 1items
OrganizationGrant numberCountry
A-STAR Singapore
CitationJournal: PLoS ONE / Year: 2017
Title: Structure-activity studies of Mdm2/Mdm4-binding stapled peptides comprising non-natural amino acids.
Authors: Chee, S.M.Q. / Wongsantichon, J. / Siau, J. / Thean, D. / Ferrer, F. / Robinson, R.C. / Lane, D.P. / Brown, C.J. / Ghadessy, F.J.
History
DepositionJul 4, 2017Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Dec 27, 2017Provider: repository / Type: Initial release
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection ...Atomic model / Data collection / Database references / Derived calculations
Category: atom_site / chem_comp_atom ...atom_site / chem_comp_atom / chem_comp_bond / database_2 / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 2.1Nov 22, 2023Group: Refinement description / Category: pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
B: E3 ubiquitin-protein ligase Mdm2
C: Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2
D: Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2


Theoretical massNumber of molelcules
Total (without water)30,3804
Polymers30,3804
Non-polymers00
Water2,234124
1
A: E3 ubiquitin-protein ligase Mdm2
C: Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2


Theoretical massNumber of molelcules
Total (without water)15,1902
Polymers15,1902
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1390 Å2
ΔGint-16 kcal/mol
Surface area6090 Å2
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
D: Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2


Theoretical massNumber of molelcules
Total (without water)15,1902
Polymers15,1902
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint-16 kcal/mol
Surface area5940 Å2
MethodPISA
Unit cell
Length a, b, c (Å)65.520, 106.410, 39.300
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number18
Space group name H-MP21212

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Components

#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: 13689.576 Da / Num. of mol.: 2 / Fragment: UNP residues 6-125 / Mutation: M62A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: PGEX 6.1 / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide Hydrocarbon stapled peptide THC-SER-PHE-0EH-GLU-TYR-6CW-ALA-LEU-LEU-MK8-NH2


Mass: 1500.199 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Phage display vector pTDisp (others)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 124 / 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: 2.28 Å3/Da / Density % sol: 46.07 %
Crystal growTemperature: 289 K / Method: vapor diffusion, sitting drop / pH: 6.4
Details: 0.04M Citric acid, 0.06M Bis-Tris propane pH 6.4, 20% (v/v) PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSRRC / Beamline: BL13C1 / Wavelength: 0.975 Å
DetectorType: RAYONIX MX300-HS / Detector: CCD / Date: Oct 10, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.975 Å / Relative weight: 1
ReflectionResolution: 1.66→25.16 Å / Num. obs: 33120 / % possible obs: 99.4 % / Redundancy: 6.4 % / Biso Wilson estimate: 25.256 Å2 / Rmerge(I) obs: 0.047 / Rpim(I) all: 0.022 / Net I/σ(I): 16.6
Reflection shellResolution: 1.66→1.7 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.685 / Mean I/σ(I) obs: 2.3 / Num. unique obs: 2414 / Rpim(I) all: 0.323 / % possible all: 99

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Processing

Software
NameVersionClassification
REFMAC5.8.0158refinement
xia2data reduction
xia2data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UMN

4umn


Resolution: 1.66→25.16 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.96 / SU B: 2.052 / SU ML: 0.067 / Cross valid method: THROUGHOUT / ESU R: 0.089 / ESU R Free: 0.086 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2088 1646 5 %RANDOM
Rwork0.18749 ---
obs0.18856 31426 99.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 32.326 Å2
Baniso -1Baniso -2Baniso -3
1--3.11 Å2-0 Å2-0 Å2
2--0.6 Å2-0 Å2
3---2.5 Å2
Refinement stepCycle: 1 / Resolution: 1.66→25.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1753 0 0 124 1877
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0191791
X-RAY DIFFRACTIONr_bond_other_d0.0020.021732
X-RAY DIFFRACTIONr_angle_refined_deg1.4522.0482426
X-RAY DIFFRACTIONr_angle_other_deg0.94534009
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.795201
X-RAY DIFFRACTIONr_dihedral_angle_2_deg44.18223.97373
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.63615318
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.719158
X-RAY DIFFRACTIONr_chiral_restr0.080.2273
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.0211887
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02351
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.8412.988832
X-RAY DIFFRACTIONr_mcbond_other1.8332.99826
X-RAY DIFFRACTIONr_mcangle_it2.8894.4731031
X-RAY DIFFRACTIONr_mcangle_other2.8774.4741026
X-RAY DIFFRACTIONr_scbond_it2.4873.334959
X-RAY DIFFRACTIONr_scbond_other2.4863.334960
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other4.1524.8461396
X-RAY DIFFRACTIONr_long_range_B_refined5.70234.752027
X-RAY DIFFRACTIONr_long_range_B_other5.62234.2481997
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.66→1.703 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.299 126 -
Rwork0.294 2269 -
obs--99.01 %

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