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- PDB-4zyc: Discovery of dihydroisoquinolinone derivatives as novel inhibitor... -
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Basic information
Entry | Database: PDB / ID: 4zyc | ||||||
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Title | Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode: Hdm2 (MDM2) complexed with cpd5 | ||||||
![]() | E3 ubiquitin-protein ligase Mdm2 | ||||||
![]() | LIGASE / PPI WITH P53 / INHIBITOR COMPLEX | ||||||
Function / homology | ![]() 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 / SUMO transferase activity / negative regulation of protein processing / response to iron ion / 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 / 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 / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / proteolysis involved in protein catabolic process / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / 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 gamma radiation / 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 / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / cellular response to hypoxia / 5S rRNA binding / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / Ub-specific processing proteases / regulation of cell cycle / protein ubiquitination / 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 | ||||||
Biological species | ![]() | ||||||
Method | ![]() ![]() ![]() ![]() | ||||||
![]() | Kallen, J. | ||||||
![]() | ![]() Title: Discovery of dihydroisoquinolinone derivatives as novel inhibitors of the p53-MDM2 interaction with a distinct binding mode. Authors: Gessier, F. / Kallen, J. / Jacoby, E. / Chene, P. / Stachyra-Valat, T. / Ruetz, S. / Jeay, S. / Holzer, P. / Masuya, K. / Furet, P. | ||||||
History |
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Structure visualization
Structure viewer | Molecule: ![]() ![]() |
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Downloads & links
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Download
PDBx/mmCIF format | ![]() | 70.7 KB | Display | ![]() |
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PDB format | ![]() | 52.5 KB | Display | ![]() |
PDBx/mmJSON format | ![]() | Tree view | ![]() | |
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-Validation report
Summary document | ![]() | 1.4 MB | Display | ![]() |
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Full document | ![]() | 1.4 MB | Display | |
Data in XML | ![]() | 13.2 KB | Display | |
Data in CIF | ![]() | 17.7 KB | Display | |
Arichive directory | ![]() ![]() | HTTPS FTP |
-Related structure data
Related structure data | ![]() 4dijS S: Starting model for refinement |
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Similar structure data |
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Links
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Assembly
Deposited unit | ![]()
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3 | ![]()
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Unit cell |
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Components
#1: Protein | Mass: 11172.008 Da / Num. of mol.: 3 Fragment: N-TERMINAL DOMAIN, P53-BINDING DOMAIN, UNP residues 17-111 Mutation: L33E Source method: isolated from a genetically manipulated source Source: (gene. exp.) ![]() ![]() ![]() References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases) #2: Chemical | #3: Chemical | ChemComp-SO4 / | #4: Water | ChemComp-HOH / | |
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-Experimental details
-Experiment
Experiment | Method: ![]() |
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Sample preparation
Crystal | Density Matthews: 0 Å3/Da / Density % sol: 0 % |
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Crystal grow | Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 8 Details: reservoir: 2.2M ammonium sulphate, 0.2M KNa tartrate, protein: 10mg/ml Hdm2 in 50mM TRIS pH 8.0, 200mM NaCl, 1mM TCEP, 10% glycerol, drop: 0.2ul reservoir + 0.2ul protein PH range: 8 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: ![]() ![]() ![]() |
Detector | Type: MARRESEARCH / Detector: CCD / Date: Nov 7, 2008 |
Radiation | Monochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 0.9794 Å / Relative weight: 1 |
Reflection | Resolution: 1.95→20 Å / Num. obs: 21169 / % possible obs: 99.8 % / Redundancy: 5.3 % / Rmerge(I) obs: 0.056 / Χ2: 0.979 / Net I/av σ(I): 31.07 / Net I/σ(I): 31.07 / Num. measured all: 112750 |
Reflection shell | Resolution: 1.95→2.02 Å / Redundancy: 5.3 % / Rmerge(I) obs: 0.25 / Mean I/σ(I) obs: 4.21 / Num. unique all: 2147 / Χ2: 1.789 / Rejects: 0 / % possible all: 100 |
-Phasing
Phasing | Method: ![]() |
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Processing
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Refinement | Method to determine structure: ![]() Starting model: 4DIJ Resolution: 1.95→20 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.921 / WRfactor Rfree: 0.2718 / WRfactor Rwork: 0.2326 / FOM work R set: 0.8309 / SU B: 3.718 / SU ML: 0.11 / SU R Cruickshank DPI: 0.2044 / SU Rfree: 0.1754 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.204 / ESU R Free: 0.175 / Stereochemistry target values: MAXIMUM LIKELIHOOD Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
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Solvent computation | Ion probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK | |||||||||||||||||||||||||||||||||||||||||||||
Displacement parameters | Biso max: 73.82 Å2 / Biso mean: 30.121 Å2 / Biso min: 16.48 Å2
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Refinement step | Cycle: final / Resolution: 1.95→20 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.95→2 Å / Total num. of bins used: 20
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