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- PDB-4j3e: The 1.9A crystal structure of humanized Xenopus Mdm2 with nutlin-3a -

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Basic information

Entry
Database: PDB / ID: 4j3e
TitleThe 1.9A crystal structure of humanized Xenopus Mdm2 with nutlin-3a
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/ANTAGONIST / Mdm2 / protein-protein interaction / imidazoline / ligase-antagonist complex / E3 ubiquitin ligase / p53 / nucleus
Function / homology
Function and homology information


regulation of biological quality / RING-type E3 ubiquitin transferase / ubiquitin protein ligase activity / p53 binding / regulation of gene expression / regulation of cell cycle / protein ubiquitination / negative regulation of apoptotic process / nucleolus / apoptotic process ...regulation of biological quality / RING-type E3 ubiquitin transferase / ubiquitin protein ligase activity / p53 binding / regulation of gene expression / regulation of cell cycle / protein ubiquitination / negative regulation of apoptotic process / nucleolus / apoptotic process / nucleoplasm / identical protein binding / nucleus / metal ion binding / cytoplasm
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-NUT / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.91 Å
AuthorsGraves, B.J. / Lukacs, C.M. / Kammlott, R.U. / Crowther, R.
Citation
Journal: ACS Med Chem Lett / Year: 2013
Title: Discovery of RG7112: A Small-Molecule MDM2 Inhibitor in Clinical Development.
Authors: Vu, B. / Wovkulich, P. / Pizzolato, G. / Lovey, A. / Ding, Q. / Jiang, N. / Liu, J.J. / Zhao, C. / Glenn, K. / Wen, Y. / Tovar, C. / Packman, K. / Vassilev, L. / Graves, B.
#1: Journal: Cancer Res. / Year: 2013
Title: MDM2 Small-Molecule Antagonist RG7112 Activates p53 Signaling and Regresses Human Tumors in Preclinical Cancer Models.
Authors: Tovar, C. / Graves, B. / Packman, K. / Filipovic, Z. / Xia, B.H. / Tardell, C. / Garrido, R. / Lee, E. / Kolinsky, K. / To, K.H. / Linn, M. / Podlaski, F. / Wovkulich, P. / Vu, B. / Vassilev, L.T.
#2: Journal: Science / Year: 2004
Title: In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.
Authors: Vassilev, L.T. / Vu, B.T. / Graves, B. / Carvajal, D. / Podlaski, F. / Filipovic, Z. / Kong, N. / Kammlott, U. / Lukacs, C. / Klein, C. / Fotouhi, N. / Liu, E.A.
History
DepositionFeb 5, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 24, 2013Provider: repository / Type: Initial release
Revision 1.1Oct 8, 2014Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references / Derived calculations
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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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)10,6403
Polymers9,9631
Non-polymers6782
Water2,306128
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)42.887, 67.657, 67.173
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-423-

HOH

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Components

#1: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Xdm2 / p53-binding protein Mdm2


Mass: 9962.615 Da / Num. of mol.: 1 / Fragment: N-terminal domain (UNP residues 21-105) / Mutation: I50L, P92H, L95I
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Xenopus laevis (African clawed frog) / Gene: mdm2 / Plasmid: PUBS 520 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21
References: UniProt: P56273, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-NUT / 4-({(4S,5R)-4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one / Nutlin 3a


Mass: 581.490 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H30Cl2N4O4
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 128 / 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: 2.45 Å3/Da / Density % sol: 49.7 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 100 mM ADA, pH 6, 50% SATURATED AMMONIUM SULFATE, 5% PEG200, 5 mM DTT RESERVOIR MIXED IN EQUAL VOLUME WITH THE PROTEIN AT 10 mg/mL, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X8C / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Apr 19, 2004
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.91→50 Å / Num. obs: 7488 / % possible obs: 95.3 % / Observed criterion σ(F): 0 / Redundancy: 3.8 % / Biso Wilson estimate: 10.1 Å2 / Rmerge(I) obs: 0.039 / Net I/σ(I): 46.1
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.91-1.982.90.06429.8185.9
4.11-503.90.0353.8189.8
3.27-4.1140.03454.2194.7
2.85-3.2740.03653196.2
2.59-2.8540.03950.4197.2
2.41-2.5940.04550.6197.4
2.26-2.4140.05147.8197.8
2.15-2.2640.05645.7197.9
2.06-2.153.90.05942.3198.6
1.98-2.063.60.0637.9198.2

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Processing

Software
NameVersionClassification
HKL-2000data collection
MOLREPphasing
CNX2005refinement
HKL-2000data reduction
HKL-2000data scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.91→24.63 Å / Rfactor Rfree error: 0.012 / Data cutoff high absF: 1199476.88 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.239 384 5.1 %RANDOM
Rwork0.194 ---
obs0.196 7488 95.6 %-
all-7488 --
Solvent computationSolvent model: FLAT MODEL / Bsol: 46.8571 Å2 / ksol: 0.355977 e/Å3
Displacement parametersBiso mean: 14.6 Å2
Baniso -1Baniso -2Baniso -3
1--0.59 Å20 Å20 Å2
2---0.39 Å20 Å2
3---0.98 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.26 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.13 Å0.05 Å
Refinement stepCycle: LAST / Resolution: 1.91→24.63 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms698 0 45 128 871
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg1.1
X-RAY DIFFRACTIONc_dihedral_angle_d20.9
X-RAY DIFFRACTIONc_improper_angle_d1.13
X-RAY DIFFRACTIONc_mcbond_it1.41.5
X-RAY DIFFRACTIONc_mcangle_it2.162
X-RAY DIFFRACTIONc_scbond_it2.242
X-RAY DIFFRACTIONc_scangle_it3.22.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shell

Refine-ID: X-RAY DIFFRACTION

Resolution (Å)Rfactor RfreeNum. reflection Rfree% reflection Rfree (%)Rfactor RworkNum. reflection RworkNum. reflection obs
1.91-20.238480.17785
2-2.10.243540.192901
2.1-2.230.293420.206904
2.23-2.410.226480.196894
2.41-2.650.233480.189910
2.65-3.030.293460.206900
3.03-3.820.224480.187906
3.82-500.214506.10.196985904
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1protein_rep.paraprotein.top
X-RAY DIFFRACTION2water_rep.paramwater.top
X-RAY DIFFRACTION3ion.paramion.top
X-RAY DIFFRACTION4RO4435385.prxRO4435385.tpx

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