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Yorodumi- PDB-4zyi: Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhi... -
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-Basic information
Entry | Database: PDB / ID: 4zyi | ||||||
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Title | Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with cpd2 | ||||||
Components | E3 ubiquitin-protein ligase Mdm2 | ||||||
Keywords | CELL CYCLE / PPI WITH P53 / INHIBITOR COMPLEX | ||||||
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 / NEDD8 ligase activity / SUMO transferase 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 / 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 / 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 / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of TP53 Degradation / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of gene expression / 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 | ||||||
Biological species | Homo sapiens (human) | ||||||
Method | X-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.67 Å | ||||||
Authors | Kallen, J. | ||||||
Citation | Journal: J.Med.Chem. / Year: 2015 Title: Discovery of a Dihydroisoquinolinone Derivative (NVP-CGM097): A Highly Potent and Selective MDM2 Inhibitor Undergoing Phase 1 Clinical Trials in p53wt Tumors. Authors: Holzer, P. / Masuya, K. / Furet, P. / Kallen, J. / Valat-Stachyra, T. / Ferretti, S. / Berghausen, J. / Bouisset-Leonard, M. / Buschmann, N. / Pissot-Soldermann, C. / Rynn, C. / Ruetz, S. / ...Authors: Holzer, P. / Masuya, K. / Furet, P. / Kallen, J. / Valat-Stachyra, T. / Ferretti, S. / Berghausen, J. / Bouisset-Leonard, M. / Buschmann, N. / Pissot-Soldermann, C. / Rynn, C. / Ruetz, S. / Stutz, S. / Chene, P. / Jeay, S. / Gessier, F. | ||||||
History |
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-Structure visualization
Structure viewer | Molecule: MolmilJmol/JSmol |
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-Downloads & links
-Download
PDBx/mmCIF format | 4zyi.cif.gz | 36 KB | Display | PDBx/mmCIF format |
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PDB format | pdb4zyi.ent.gz | 22.9 KB | Display | PDB format |
PDBx/mmJSON format | 4zyi.json.gz | Tree view | PDBx/mmJSON format | |
Others | Other downloads |
-Validation report
Arichive directory | https://data.pdbj.org/pub/pdb/validation_reports/zy/4zyi ftp://data.pdbj.org/pub/pdb/validation_reports/zy/4zyi | HTTPS FTP |
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-Related structure data
Related structure data | 4zyfC 4zycS S: Starting model for refinement C: citing same article (ref.) |
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Similar structure data |
-Links
-Assembly
Deposited unit |
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1 |
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Unit cell |
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Components on special symmetry positions |
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-Components
#1: Protein | Mass: 11156.052 Da / Num. of mol.: 1 Fragment: N-TERMINAL DOMAIN, P53-BINDING DOMAIN, UNP residues 17-111 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) |
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#2: Chemical | ChemComp-4TH / ( |
#3: Chemical | ChemComp-CL / |
#4: Water | ChemComp-HOH / |
-Experimental details
-Experiment
Experiment | Method: X-RAY DIFFRACTION / Number of used crystals: 1 |
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-Sample preparation
Crystal | Density Matthews: 2.16 Å3/Da / Density % sol: 43 % |
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Crystal grow | Temperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.7 Details: reservoir: 2.2M AmmoniumSulfate, 0.1M cictric acid, pH4.7. protein: 7mg/ml Hdm2 in 50mM TRIS pH8.0, 200mM NaCl, 1mM TCEP, 10% glycerol. drop: 1ul reservoir + 1ul protein PH range: 4.7 |
-Data collection
Diffraction | Mean temperature: 100 K |
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Diffraction source | Source: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.00001 Å |
Detector | Type: MARRESEARCH / Detector: CCD / Date: Feb 13, 2009 |
Radiation | Monochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray |
Radiation wavelength | Wavelength: 1.00001 Å / Relative weight: 1 |
Reflection | Resolution: 1.67→20 Å / Num. obs: 12116 / % possible obs: 99.9 % / Redundancy: 33.9 % / Rmerge(I) obs: 0.047 / Χ2: 0.967 / Net I/av σ(I): 94.144 / Net I/σ(I): 94.14 / Num. measured all: 410905 |
Reflection shell | Resolution: 1.67→1.73 Å / Redundancy: 23.4 % / Rmerge(I) obs: 0.34 / Mean I/σ(I) obs: 7.49 / Num. unique all: 1346 / Χ2: 1.685 / Rejects: 0 / % possible all: 100 |
-Processing
Software |
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Refinement | Method to determine structure: MOLECULAR REPLACEMENT Starting model: 4ZYC Resolution: 1.67→20 Å / Cor.coef. Fo:Fc: 0.94 / Cor.coef. Fo:Fc free: 0.94 / SU B: 2.334 / SU ML: 0.079 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.131 / ESU R Free: 0.114 / 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: 60.86 Å2 / Biso mean: 27.286 Å2 / Biso min: 13.6 Å2
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Refinement step | Cycle: final / Resolution: 1.67→20 Å
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Refine LS restraints |
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LS refinement shell | Resolution: 1.67→1.713 Å / Total num. of bins used: 20
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