[English] 日本語
Yorodumi
- PDB-5lay: Discovery of New Natural-product-inspired Spiro-oxindole Compound... -

+
Open data


ID or keywords:

Loading...

-
Basic information

Entry
Database: PDB / ID: 5lay
TitleDiscovery of New Natural-product-inspired Spiro-oxindole Compounds as Orally Active Inhibitors of the MDM2-p53 Interaction: HDM2 (MDM2) IN COMPLEX WITH COMPOUND 6g
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / VIENNA / PPI / MDM2 / HDM2 / BI
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / response to ether / traversing start control point of mitotic cell cycle / 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 / response to ether / traversing start control point of mitotic cell cycle / 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 / response to iron ion / peroxisome proliferator activated receptor binding / negative regulation of protein processing / response to steroid hormone / SUMO transferase activity / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / 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 / response to magnesium ion / ligase activity / protein sumoylation / SUMOylation of transcription factors / protein localization to nucleus / cellular response to actinomycin D / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of vascular associated smooth muscle cell proliferation / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / cellular response to gamma radiation / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / 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 / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / 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 / protein ubiquitination / regulation of cell cycle / 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 / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm / identical protein 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
Chem-6SS / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.71 Å
AuthorsKessler, D. / Gollner, A.
CitationJournal: J. Med. Chem. / Year: 2016
Title: Discovery of Novel Spiro[3H-indole-3,2'-pyrrolidin]-2(1H)-one Compounds as Chemically Stable and Orally Active Inhibitors of the MDM2-p53 Interaction.
Authors: Gollner, A. / Rudolph, D. / Arnhof, H. / Bauer, M. / Blake, S.M. / Boehmelt, G. / Cockroft, X.L. / Dahmann, G. / Ettmayer, P. / Gerstberger, T. / Karolyi-Oezguer, J. / Kessler, D. / Kofink, ...Authors: Gollner, A. / Rudolph, D. / Arnhof, H. / Bauer, M. / Blake, S.M. / Boehmelt, G. / Cockroft, X.L. / Dahmann, G. / Ettmayer, P. / Gerstberger, T. / Karolyi-Oezguer, J. / Kessler, D. / Kofink, C. / Ramharter, J. / Rinnenthal, J. / Savchenko, A. / Schnitzer, R. / Weinstabl, H. / Weyer-Czernilofsky, U. / Wunberg, T. / McConnell, D.B.
History
DepositionJun 15, 2016Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 2, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 21, 2016Group: Database references
Revision 1.2Jun 12, 2019Group: Advisory / Data collection / Structure summary
Category: audit_author / database_PDB_rev ...audit_author / database_PDB_rev / database_PDB_rev_record / pdbx_unobs_or_zero_occ_atoms
Item: _audit_author.name
Revision 1.3May 8, 2024Group: Advisory / Data collection / Database references
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_unobs_or_zero_occ_atoms
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

-
Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

-
Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
B: E3 ubiquitin-protein ligase Mdm2
C: E3 ubiquitin-protein ligase Mdm2
D: E3 ubiquitin-protein ligase Mdm2
E: E3 ubiquitin-protein ligase Mdm2
F: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)70,52521
Polymers66,5946
Non-polymers3,93115
Water1,76598
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,9866
Polymers11,0991
Non-polymers8875
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7093
Polymers11,0991
Non-polymers6102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7063
Polymers11,0991
Non-polymers6072
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,7093
Polymers11,0991
Non-polymers6102
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8024
Polymers11,0991
Non-polymers7033
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6132
Polymers11,0991
Non-polymers5141
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)71.450, 71.450, 520.977
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number179
Space group name H-MP6522

-
Components

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


Mass: 11099.000 Da / Num. of mol.: 6 / Fragment: TRUNCATED N-TERMINAL DOMAIN / Source method: isolated from a natural source / Details: EXTERNAL / Source: (natural) Homo sapiens (human)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical
ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C3H8O3
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-6SS / (3~{S},3'~{S},4'~{S},5'~{S})-4'-azanyl-6-chloranyl-3'-(3-chloranyl-2-fluoranyl-phenyl)-1'-[(3-ethoxyphenyl)methyl]-5'-methyl-spiro[1~{H}-indole-3,2'-pyrrolidine]-2-one


Mass: 514.419 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C27H26Cl2FN3O2
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 98 / Source method: isolated from a natural source / Formula: H2O

-
Experimental details

-
Experiment

ExperimentMethod: X-RAY DIFFRACTION / Number of used crystals: 1

-
Sample preparation

CrystalDensity Matthews: 2.99 Å3/Da / Density % sol: 58.93 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 4.5 / Details: NULL

-
Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 6, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.7→87.45 Å / Num. obs: 22692 / % possible obs: 99 % / Observed criterion σ(I): 0 / Redundancy: 6.2 % / Rsym value: 0.163 / Net I/σ(I): 11.89
Reflection shellResolution: 2.71→2.96 Å / Redundancy: 6.7 % / Rsym value: 0.448 / % possible all: 99.6

-
Processing

Software
NameVersionClassification
REFMAC5.6.0117refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
XSCALEdata scaling
REFMACphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.71→87.45 Å / Cor.coef. Fo:Fc: 0.87 / Cor.coef. Fo:Fc free: 0.826 / SU B: 30.599 / SU ML: 0.314 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.874 / ESU R Free: 0.373
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : RESIDUAL ONLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2917 806 3.6 %RANDOM
Rwork0.2506 ---
obs0.2521 21885 98.96 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 78.45 Å2 / Biso mean: 6.664 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.46 Å20.23 Å20 Å2
2--0.46 Å20 Å2
3----0.7 Å2
Refinement stepCycle: final / Resolution: 2.71→87.45 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4547 0 260 98 4905
Biso mean--14.87 20.44 -
Num. residues----552
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.024741
X-RAY DIFFRACTIONr_bond_other_d0.0010.023244
X-RAY DIFFRACTIONr_angle_refined_deg1.1322.0526464
X-RAY DIFFRACTIONr_angle_other_deg1.37337823
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.3345555
X-RAY DIFFRACTIONr_dihedral_angle_2_deg39.00223.779172
X-RAY DIFFRACTIONr_dihedral_angle_3_deg13.63915791
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.8381519
X-RAY DIFFRACTIONr_chiral_restr0.0570.2742
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.0215054
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02941
LS refinement shellResolution: 2.71→2.78 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.375 51 -
Rwork0.324 1304 -
all-1355 -
obs--99.56 %

+
About Yorodumi

-
News

-
Feb 9, 2022. New format data for meta-information of EMDB entries

New format data for meta-information of EMDB entries

  • Version 3 of the EMDB header file is now the official format.
  • The previous official version 1.9 will be removed from the archive.

Related info.:EMDB header

External links:wwPDB to switch to version 3 of the EMDB data model

-
Aug 12, 2020. Covid-19 info

Covid-19 info

URL: https://pdbj.org/emnavi/covid19.php

New page: Covid-19 featured information page in EM Navigator.

Related info.:Covid-19 info / Mar 5, 2020. Novel coronavirus structure data

+
Mar 5, 2020. Novel coronavirus structure data

Novel coronavirus structure data

Related info.:Yorodumi Speices / Aug 12, 2020. Covid-19 info

External links:COVID-19 featured content - PDBj / Molecule of the Month (242)：Coronavirus Proteases

+
Jan 31, 2019. EMDB accession codes are about to change! (news from PDBe EMDB page)

EMDB accession codes are about to change! (news from PDBe EMDB page)

  • The allocation of 4 digits for EMDB accession codes will soon come to an end. Whilst these codes will remain in use, new EMDB accession codes will include an additional digit and will expand incrementally as the available range of codes is exhausted. The current 4-digit format prefixed with “EMD-” (i.e. EMD-XXXX) will advance to a 5-digit format (i.e. EMD-XXXXX), and so on. It is currently estimated that the 4-digit codes will be depleted around Spring 2019, at which point the 5-digit format will come into force.
  • The EM Navigator/Yorodumi systems omit the EMD- prefix.

Related info.:Q: What is EMD? / ID/Accession-code notation in Yorodumi/EM Navigator

External links:EMDB Accession Codes are Changing Soon! / Contact to PDBj

+
Jul 12, 2017. Major update of PDB

Major update of PDB

  • wwPDB released updated PDB data conforming to the new PDBx/mmCIF dictionary.
  • This is a major update changing the version number from 4 to 5, and with Remediation, in which all the entries are updated.
  • In this update, many items about electron microscopy experimental information are reorganized (e.g. em_software).
  • Now, EM Navigator and Yorodumi are based on the updated data.

External links:wwPDB Remediation / Enriched Model Files Conforming to OneDep Data Standards Now Available in the PDB FTP Archive

-
Yorodumi

Thousand views of thousand structures

  • Yorodumi is a browser for structure data from EMDB, PDB, SASBDB, etc.
  • This page is also the successor to EM Navigator detail page, and also detail information page/front-end page for Omokage search.
  • The word "yorodu" (or yorozu) is an old Japanese word meaning "ten thousand". "mi" (miru) is to see.

Related info.:EMDB / PDB / SASBDB / Comparison of 3 databanks / Yorodumi Search / Aug 31, 2016. New EM Navigator & Yorodumi / Yorodumi Papers / Jmol/JSmol / Function and homology information / Changes in new EM Navigator and Yorodumi

Read more