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- PDB-4zyf: Discovery of NVP-CGM097 - a highly potent and selective MDM2 inhi... -

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Basic information

Entry
Database: PDB / ID: 4zyf
TitleDiscovery of NVP-CGM097 - a highly potent and selective MDM2 inhibitor undergoing phase 1 clinical trials in p53wt tumors: Hdm2 (MDM2) complexed with NVP-CGM097
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsCELL 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 / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / 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 / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / receptor serine/threonine kinase binding / peroxisome proliferator activated receptor binding / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / response to iron ion / atrioventricular valve morphogenesis / endocardial cushion morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / positive regulation of muscle cell differentiation / cardiac septum morphogenesis / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / blood vessel development / ligase activity / cellular response to alkaloid / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of signal transduction by p53 class mediator / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / cellular response to UV-C / protein sumoylation / cellular response to actinomycin D / blood vessel remodeling / cellular response to estrogen stimulus / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / positive regulation of mitotic cell cycle / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / ubiquitin binding / response to cocaine / DNA damage response, signal transduction by p53 class mediator / Stabilization of p53 / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / Oncogene Induced Senescence / protein destabilization / RING-type E3 ubiquitin transferase / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / response to toxic substance / centriolar satellite / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / p53 binding / ubiquitin protein ligase activity / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / 5S rRNA binding / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / Ub-specific processing proteases / postsynaptic density / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / apoptotic process / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / glutamatergic synapse / enzyme binding
Similarity search - Function
E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 ...E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 superfamily / Zinc finger RanBP2-type signature. / 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-4T4 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsKallen, J.
CitationJournal: 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
DepositionMay 21, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jul 29, 2015Provider: repository / Type: Initial release
Revision 1.1Aug 5, 2015Group: Non-polymer description
Revision 1.2Sep 9, 2015Group: Database references
Revision 1.3Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / diffrn_radiation_wavelength / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8513
Polymers11,1561
Non-polymers6952
Water1,17165
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)55.609, 55.609, 108.280
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-202-

CL

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Components

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


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)
#2: Chemical ChemComp-4T4 / (S)-1-(4-chlorophenyl)-7-isopropoxy-6-methoxy-2-(4-(methyl(((1r,4S)-4-(4-methyl-3-oxopiperazin-1-yl)cyclohexyl)methyl)amino)phenyl)-1,2-dihydroisoquinolin-3(4H)-one / NVP-CGM097


Mass: 659.257 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H47ClN4O4
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 65 / 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: 2.17 Å3/Da / Density % sol: 43.22 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 4.5
Details: reservoir: 2M AmSulfate, 0.1M cictric acid, pH4.5, protein: 7mg/ml Hdm2 in 50mM TRIS pH8.0, 200mM NaCl, 1mM TCEP, 10% glycerol, drop: 1ul reservoir + 1ul protein
PH range: 4.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Apr 26, 2010
RadiationMonochromator: SI 111 CHANNEL / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.8→19.75 Å / Num. obs: 9762 / % possible obs: 99.9 % / Observed criterion σ(I): -3 / Redundancy: 20.4 % / Rmerge(I) obs: 0.075 / Net I/σ(I): 29.1
Reflection shellResolution: 1.8→1.85 Å / Redundancy: 19.5 % / Rmerge(I) obs: 0.629 / Mean I/σ(I) obs: 5.8 / Rejects: 0 / % possible all: 100

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.5.0063refinement
PDB_EXTRACT3.15data extraction
MOLREPphasing
APRVdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4ZYI

4zyi


Resolution: 1.8→19.75 Å / Cor.coef. Fo:Fc: 0.938 / Cor.coef. Fo:Fc free: 0.931 / SU B: 2.75 / SU ML: 0.088 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.163 / ESU R Free: 0.131 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2321 488 5 %RANDOM
Rwork0.2267 ---
obs0.227 9273 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 66.44 Å2 / Biso mean: 24.274 Å2 / Biso min: 11.39 Å2
Baniso -1Baniso -2Baniso -3
1-0.26 Å20.13 Å20 Å2
2--0.26 Å20 Å2
3----0.39 Å2
Refinement stepCycle: final / Resolution: 1.8→19.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms765 0 48 65 878
Biso mean--23.87 38.4 -
Num. residues----93
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022838
X-RAY DIFFRACTIONr_angle_refined_deg1.042.0621136
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.305594
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.96323.93933
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.1315156
X-RAY DIFFRACTIONr_dihedral_angle_4_deg15.745154
X-RAY DIFFRACTIONr_chiral_restr0.080.2126
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021607
LS refinement shellResolution: 1.8→1.846 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.198 35 -
Rwork0.272 668 -
all-703 -
obs--100 %

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