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- PDB-6y4q: Structure of a stapled peptide bound to MDM2 -

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Basic information

Entry
Database: PDB / ID: 6y4q
TitleStructure of a stapled peptide bound to MDM2
Components
  • ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / MDM2 / p53 / stapled
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 / response to magnesium ion / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / 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 / ubiquitin binding / proteolysis involved in protein catabolic process / response to cocaine / Stabilization of p53 / protein destabilization / Regulation of RUNX3 expression and activity / establishment of protein localization / RING-type E3 ubiquitin transferase / cellular response to growth factor stimulus / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to hydrogen peroxide / 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
Chem-O9E / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.63 Å
AuthorsPantelejevs, T. / Bakanovych, I.
Funding support United Kingdom, 1items
OrganizationGrant numberCountry
Medical Research Council (MRC, United Kingdom) United Kingdom
CitationJournal: Org.Biomol.Chem. / Year: 2020
Title: Diarylethene moiety as an enthalpy-entropy switch: photoisomerizable stapled peptides for modulating p53/MDM2 interaction.
Authors: Strizhak, A.V. / Babii, O. / Afonin, S. / Bakanovich, I. / Pantelejevs, T. / Xu, W. / Fowler, E. / Eapen, R. / Sharma, K. / Platonov, M.O. / Hurmach, V.V. / Itzhaki, L. / Hyvonen, M. / ...Authors: Strizhak, A.V. / Babii, O. / Afonin, S. / Bakanovich, I. / Pantelejevs, T. / Xu, W. / Fowler, E. / Eapen, R. / Sharma, K. / Platonov, M.O. / Hurmach, V.V. / Itzhaki, L. / Hyvonen, M. / Ulrich, A.S. / Spring, D.R. / Komarov, I.V.
History
DepositionFeb 22, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0May 20, 2020Provider: repository / Type: Initial release
Revision 1.1Jul 29, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID
Revision 1.2Jan 24, 2024Group: Advisory / Data collection ...Advisory / 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 / pdbx_unobs_or_zero_occ_atoms
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: E3 ubiquitin-protein ligase Mdm2
C: ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER
D: ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,3786
Polymers24,1644
Non-polymers1,2142
Water2,270126
1
A: E3 ubiquitin-protein ligase Mdm2
C: ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,6893
Polymers12,0822
Non-polymers6071
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1510 Å2
ΔGint-11 kcal/mol
Surface area5990 Å2
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
D: ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,6893
Polymers12,0822
Non-polymers6071
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1460 Å2
ΔGint-11 kcal/mol
Surface area5980 Å2
MethodPISA
Unit cell
Length a, b, c (Å)34.240, 34.840, 48.410
Angle α, β, γ (deg.)93.380, 107.380, 117.450
Int Tables number1
Space group name H-MP1

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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: 10670.497 Da / Num. of mol.: 2 / Mutation: E69A, K70A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide ACE-LEU-THR-PHE-GLY-GLU-TYR-TRP-ALA-GLN-LEU-ALA-SER


Mass: 1411.558 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-O9E / ~{N}-[(1-ethyl-1,2,3-triazol-4-yl)methyl]-~{N},5-dimethyl-4-[2-[2-methyl-5-[methyl-[(1-propyl-1,2,3-triazol-4-yl)methyl]carbamoyl]thiophen-3-yl]cyclopenten-1-yl]thiophene-2-carboxamide


Mass: 606.805 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H38N8O2S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 126 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 1.97 Å3/Da / Density % sol: 37.52 %
Crystal growTemperature: 291 K / Method: vapor diffusion
Details: 10% w/v PEG 8000 (precipitant), 0.1 M Tris-HCl pH 7.0 (buffer), 0.2 M Magnesium chloride hexahydrate (salt)

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Data collection

DiffractionMean temperature: 63 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER2 XE 16M / Detector: PIXEL / Date: Dec 2, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.63→44.93 Å / Num. obs: 21777 / % possible obs: 94.9 % / Redundancy: 3 % / Biso Wilson estimate: 24.98 Å2 / CC1/2: 0.987 / Rmerge(I) obs: 0.162 / Rpim(I) all: 0.087 / Rrim(I) all: 0.184 / Net I/σ(I): 23.3 / Num. measured all: 65928 / Scaling rejects: 8
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.63-1.721.70.462514829650.7120.4620.6544.488.6
5.16-44.935.10.14836827230.9830.0720.16560.199.9

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Processing

Software
NameVersionClassification
Aimless0.5.31data scaling
BUSTERrefinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5AFG

5afg


Resolution: 1.63→30.07 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.93 / SU R Cruickshank DPI: 0.123 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.121 / SU Rfree Blow DPI: 0.113 / SU Rfree Cruickshank DPI: 0.115
RfactorNum. reflection% reflectionSelection details
Rfree0.229 1086 4.99 %RANDOM
Rwork0.194 ---
obs0.196 21751 94.8 %-
Displacement parametersBiso max: 155.24 Å2 / Biso mean: 30.76 Å2 / Biso min: 10.94 Å2
Baniso -1Baniso -2Baniso -3
1--0.9699 Å2-4.639 Å20.5338 Å2
2---3.8332 Å23.3769 Å2
3---4.8031 Å2
Refine analyzeLuzzati coordinate error obs: 0.24 Å
Refinement stepCycle: final / Resolution: 1.63→30.07 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1704 0 84 126 1914
Biso mean--40.22 44.24 -
Num. residues----209
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d691SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes384HARMONIC5
X-RAY DIFFRACTIONt_it1938HARMONIC20
X-RAY DIFFRACTIONt_nbd
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion233SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact2541SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d1938HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg2640HARMONIC20.97
X-RAY DIFFRACTIONt_omega_torsion3.38
X-RAY DIFFRACTIONt_other_torsion18.98
LS refinement shellResolution: 1.63→1.64 Å / Rfactor Rfree error: 0 / Total num. of bins used: 50
RfactorNum. reflection% reflection
Rfree0.3857 17 3.9 %
Rwork0.2815 419 -
all0.2852 436 -
obs--84.8 %

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