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- PDB-6kzu: Macrocyclization of an all-D linear peptide improves target affin... -

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Basic information

Entry
Database: PDB / ID: 6kzu
TitleMacrocyclization of an all-D linear peptide improves target affinity and imparts cellular activity: A novel stapled alpha-helical peptide modality
Components
  • 2JN-DAL-E03-DTY-2JN-DSG-TDF-DGL-MK8-DLE-DLE-2JN
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / E3 ligase
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 / 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 / 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 / Signaling by ALK fusions and activated point mutants / establishment of protein localization / 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 / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / Ub-specific processing proteases / protein ubiquitination / regulation of cell cycle / 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 / 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
polypeptide(D) / polypeptide(D) (> 10) / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
Phage 13 (virus)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.79 Å
AuthorsJiang, S. / Brown, C.J.
CitationJournal: Chem Sci / Year: 2020
Title: Macrocyclization of an all-d linear alpha-helical peptide imparts cellular permeability.
Authors: Kannan, S. / Aronica, P.G.A. / Ng, S. / Gek Lian, D.T. / Frosi, Y. / Chee, S. / Shimin, J. / Yuen, T.Y. / Sadruddin, A. / Kaan, H.Y.K. / Chandramohan, A. / Wong, J.H. / Tan, Y.S. / Chang, Z. ...Authors: Kannan, S. / Aronica, P.G.A. / Ng, S. / Gek Lian, D.T. / Frosi, Y. / Chee, S. / Shimin, J. / Yuen, T.Y. / Sadruddin, A. / Kaan, H.Y.K. / Chandramohan, A. / Wong, J.H. / Tan, Y.S. / Chang, Z.W. / Ferrer-Gago, F.J. / Arumugam, P. / Han, Y. / Chen, S. / Renia, L. / Brown, C.J. / Johannes, C.W. / Henry, B. / Lane, D.P. / Sawyer, T.K. / Verma, C.S. / Partridge, A.W.
History
DepositionSep 25, 2019Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Oct 16, 2019Provider: repository / Type: Initial release
Revision 1.1Nov 4, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
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: 2JN-DAL-E03-DTY-2JN-DSG-TDF-DGL-MK8-DLE-DLE-2JN


Theoretical massNumber of molelcules
Total (without water)15,4002
Polymers15,4002
Non-polymers00
Water1,09961
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: surface plasmon resonance
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1220 Å2
ΔGint-6 kcal/mol
Surface area5950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.567, 82.567, 54.783
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number178
Space group name H-MP6122
Components on special symmetry positions
IDModelComponents
11A-242-

HOH

21B-201-

HOH

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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: 13749.694 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Polypeptide(D) 2JN-DAL-E03-DTY-2JN-DSG-TDF-DGL-MK8-DLE-DLE-2JN


Mass: 1649.907 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Phage 13 (virus)
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 61 / 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: 1.77 Å3/Da / Density % sol: 30.39 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 7.5
Details: 800 mM Sodium di-hydrogen phosphate, 800 mM di-Potassium hydrogen phosphate, 100 mM HEPES pH 7.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Australian Synchrotron / Beamline: MX1 / Wavelength: 0.9537 Å
DetectorType: ADSC QUANTUM 210r / Detector: CCD / Date: Oct 1, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9537 Å / Relative weight: 1
ReflectionResolution: 1.79→43.9 Å / Num. obs: 10913 / % possible obs: 100 % / Redundancy: 20.7 % / Rmerge(I) obs: 0.065 / Net I/σ(I): 25.6
Reflection shellResolution: 1.79→1.82 Å / Rmerge(I) obs: 1.745 / Mean I/σ(I) obs: 1.6 / Num. unique obs: 599 / Rpim(I) all: 0.39

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Processing

Software
NameVersionClassification
REFMAC5.8.0189refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4UMN

4umn


Resolution: 1.79→43.49 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.948 / SU B: 3.238 / SU ML: 0.098 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.139 / ESU R Free: 0.132
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2361 1092 10 %RANDOM
Rwork0.199 ---
obs0.2027 9820 99.91 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 75.04 Å2 / Biso mean: 33.102 Å2 / Biso min: 20.19 Å2
Baniso -1Baniso -2Baniso -3
1-0.57 Å20.29 Å20 Å2
2--0.57 Å2-0 Å2
3----1.86 Å2
Refinement stepCycle: final / Resolution: 1.79→43.49 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms812 0 81 61 954
Biso mean--27.44 43.4 -
Num. residues----89
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.02850
X-RAY DIFFRACTIONr_bond_other_d0.0020.02819
X-RAY DIFFRACTIONr_angle_refined_deg1.5622.1421146
X-RAY DIFFRACTIONr_angle_other_deg0.94731891
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.41585
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.2123.33330
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.98815143
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.714154
X-RAY DIFFRACTIONr_chiral_restr0.0940.2127
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.02856
X-RAY DIFFRACTIONr_gen_planes_other0.0020.02162
LS refinement shellResolution: 1.79→1.832 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.326 80 -
Rwork0.314 718 -
obs--99.75 %

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