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- PDB-3tu1: Exhaustive Fluorine Scanning towards Potent p53-MDM2 Antagonist -

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Basic information

Entry
Database: PDB / ID: 3tu1
TitleExhaustive Fluorine Scanning towards Potent p53-MDM2 Antagonist
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / p53-binding protein Mdm2 / Oncoprotein Mdm2 / Double minute 2 protein / Hdm2 / oncoprotein / p53 / nucleus
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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / ligase 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 / 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 / regulation of cell cycle / protein ubiquitination / Ub-specific processing proteases / 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
Chem-07G / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.603 Å
AuthorsWolf, S. / Huang, Y. / Koes, D. / Popowicz, G.M. / Camacho, C.J. / Holak, T.A. / Doemling, A.
CitationJournal: Chemmedchem / Year: 2012
Title: Exhaustive Fluorine Scanning toward Potent p53-Mdm2 Antagonists.
Authors: Huang, Y. / Wolf, S. / Koes, D. / Popowicz, G.M. / Camacho, C.J. / Holak, T.A. / Domling, A.
History
DepositionSep 15, 2011Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 2, 2011Provider: repository / Type: Initial release
Revision 1.1Jan 18, 2012Group: Database references
Revision 1.2Nov 8, 2017Group: Refinement description / Category: software / Item: _software.name
Revision 1.3Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id
Revision 2.0May 29, 2024Group: Data collection / Derived calculations ...Data collection / Derived calculations / Non-polymer description / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / entity / pdbx_entity_nonpoly / pdbx_validate_chiral
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _entity.formula_weight / _entity.pdbx_description / _pdbx_entity_nonpoly.name

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,9262
Polymers12,4481
Non-polymers4781
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)49.950, 59.250, 82.950
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number23
Space group name H-MI222
Components on special symmetry positions
IDModelComponents
11A-14-

HOH

21A-161-

HOH

31A-170-

HOH

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Components

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


Mass: 12448.272 Da / Num. of mol.: 1 / Fragment: p53 binding domain (UNP Residues 18-105)
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, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-07G / 3-[(1S)-2-(tert-butylamino)-1-{N-[(3,4-difluorophenyl)methyl]formamido}-2-oxoethyl]-6-chloro-1H-indole-2-carboxylic acid


Mass: 477.888 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H22ClF2N3O4
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.47 Å3/Da / Density % sol: 50.1 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 4.8
Details: 0.1 M sodium acetate 18% PEG 4000 , pH 4.8, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 7, 2011
RadiationMonochromator: LN2 cooled fixed-exit Si(111) monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.6→50 Å / Num. all: 16540 / Num. obs: 12505
Reflection shellResolution: 1.6→1.75 Å / % possible all: 97.5

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Processing

Software
NameVersionClassification
MAR345data collection
XFITdata reduction
REFMAC5.5.0072refinement
XDSdata reduction
XSCALEdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.603→20 Å / Cor.coef. Fo:Fc: 0.951 / Cor.coef. Fo:Fc free: 0.929 / SU B: 5.141 / SU ML: 0.078 / Cross valid method: THROUGHOUT / ESU R: 0.178 / ESU R Free: 0.12 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24455 628 5 %RANDOM
Rwork0.20455 ---
obs0.20642 11877 75.72 %-
all-16540 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 18.255 Å2
Baniso -1Baniso -2Baniso -3
1-0.95 Å20 Å20 Å2
2---2.24 Å20 Å2
3---1.29 Å2
Refinement stepCycle: LAST / Resolution: 1.603→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms750 0 33 116 899
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022800
X-RAY DIFFRACTIONr_bond_other_d0.0020.02532
X-RAY DIFFRACTIONr_angle_refined_deg1.4672.0331087
X-RAY DIFFRACTIONr_angle_other_deg0.8993.0041292
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.474592
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.52724.19431
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.96815143
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.314153
X-RAY DIFFRACTIONr_chiral_restr0.2480.2123
X-RAY DIFFRACTIONr_gen_planes_refined0.0060.021851
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02149
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_it0.5691.5464
X-RAY DIFFRACTIONr_mcbond_other0.1751.5185
X-RAY DIFFRACTIONr_mcangle_it1.052757
X-RAY DIFFRACTIONr_scbond_it1.5223336
X-RAY DIFFRACTIONr_scangle_it2.5174.5330
X-RAY DIFFRACTIONr_rigid_bond_restr0.79331332
X-RAY DIFFRACTIONr_sphericity_free2.0963116
X-RAY DIFFRACTIONr_sphericity_bonded1.1731315
LS refinement shellResolution: 1.603→1.645 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.293 16 -
Rwork0.206 329 -
obs--28.63 %

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