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- PDB-4j74: The 1.2A crystal structure of humanized Xenopus MDM2 with RO05039... -

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Basic information

Entry
Database: PDB / ID: 4j74
TitleThe 1.2A crystal structure of humanized Xenopus MDM2 with RO0503918 - a nutlin fragment
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/ANTAGONIST / MDM2 / IMIDAZOLINE / LIGASE-ANTAGONIST COMPLEX / E3 UBIQUITIN LIGASE / P53 / NUCLEUS
Function / homology
Function and homology information


regulation of biological quality / positive regulation of mitotic cell cycle / RING-type E3 ubiquitin transferase / p53 binding / ubiquitin protein ligase activity / regulation of gene expression / ubiquitin-dependent protein catabolic process / protein ubiquitination / apoptotic process / negative regulation of apoptotic process ...regulation of biological quality / positive regulation of mitotic cell cycle / RING-type E3 ubiquitin transferase / p53 binding / ubiquitin protein ligase activity / regulation of gene expression / ubiquitin-dependent protein catabolic process / protein ubiquitination / apoptotic process / negative regulation of apoptotic process / nucleolus / zinc ion binding / nucleoplasm / identical protein binding / nucleus / cytoplasm
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-I18 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsJanson, C. / Lukacs, C. / Kammlott, U. / Graves, B.
Citation
Journal: ACS Med Chem Lett / Year: 2013
Title: Deconstruction of a nutlin: dissecting the binding determinants of a potent protein-protein interaction inhibitor.
Authors: Fry, D.C. / Wartchow, C. / Graves, B. / Janson, C. / Lukacs, C. / Kammlott, U. / Belunis, C. / Palme, S. / Klein, C. / Vu, B.
#1: Journal: To be Published
Title: Discovery of RG7112: a small-molecule MDM2 antagonist in clinical development
Authors: Vu, B. / Wovkulich, P. / Pizzolato, G. / Jiang, N. / Ding, Q. / Liu, J.-J. / Lovey, A. / Zhao, C. / Glenn, K. / Wen, Y. / Tovar, C. / Thompson, T. / Vassilev, L. / Graves, B.
#2: Journal: To be Published
Title: MDM2 antagonist, RG7112, activates P53 signalling and regresses human tumors in preclinical cancer models
Authors: Tovar, C. / Graves, B. / Packman, K. / Filipovic, Z. / Higgins, B. / Xia, M. / Tardell, C. / Garrido, R. / Lee, E. / Linn, M. / Podlaski, F. / Wovkulich, P. / Vu, B. / Vassilev, L.T.
#3: 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 12, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2013Provider: repository / Type: Initial release
Revision 1.1Sep 24, 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

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)10,6694
Polymers9,9631
Non-polymers7063
Water2,090116
1


  • Idetical with deposited unit
  • defined by author
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)42.950, 68.554, 67.183
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
DetailsTHE N-TERMINAL DOMAIN OF MDM2 EXISTS AS A MONOMER WHILE THE FULL-LENGTH MOLECULE FORMS DIMERS

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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-I18 / (4S,5R)-4,5-bis(4-chlorophenyl)-2-methyl-4,5-dihydro-1H-imidazole


Mass: 305.202 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H14Cl2N2
#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.: 116 / 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: 2.48 Å3/Da / Density % sol: 50.44 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 40-50% SATURATED AMMONIUM SULFATE, 0.1M MES, PH 6.5, 5% PEG200, VAPOR DIFFUSION, HANGING DROP, temperature 278.0K

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Data collection

DiffractionMean temperature: 77 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Aug 21, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.12→65 Å / Num. obs: 34640 / % possible obs: 93.3 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.1 % / Biso Wilson estimate: 11.2 Å2 / Rmerge(I) obs: 0.058 / Net I/σ(I): 5.5
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
1.12-1.185.90.5121.54309178.7
3.55-655.60.03415.31301199
2.51-3.556.10.04411.92236199
2.05-2.515.80.0587.62866198.9
1.77-2.056.20.069.13329198.4
1.59-1.775.80.0779.23759197.6
1.45-1.596.40.1196.34079197
1.34-1.456.20.1983.84381195.8
1.25-1.346.50.2912.64584193.2
1.18-1.256.20.3924701190.5

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Processing

Software
NameVersionClassification
MOLREPphasing
CNX2005refinement
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.2→36.4 Å / Rfactor Rfree error: 0.006 / Data cutoff high absF: 1760342.39 / 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
Rfree0.241 1456 4.9 %RANDOM
Rwork0.229 ---
all0.23 29710 --
obs0.229 29710 94.6 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 53.6119 Å2 / ksol: 0.389868 e/Å3
Displacement parametersBiso mean: 16.3 Å2
Baniso -1Baniso -2Baniso -3
1--3.74 Å20 Å20 Å2
2--5.07 Å20 Å2
3----1.33 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.18 Å0.17 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.15 Å
Refinement stepCycle: LAST / Resolution: 1.2→36.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms698 0 45 116 859
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.005
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d20
X-RAY DIFFRACTIONc_improper_angle_d0.82
X-RAY DIFFRACTIONc_mcbond_it1.121.5
X-RAY DIFFRACTIONc_mcangle_it1.732
X-RAY DIFFRACTIONc_scbond_it2.092
X-RAY DIFFRACTIONc_scangle_it3.062.5
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
1.2-1.210.4169330.3264893
1.21-1.230.2854450.3084928
1.23-1.240.3805470.3271892
1.24-1.260.3212430.3001937
1.26-1.280.2777470.295895
1.28-1.30.2845490.2814945
1.3-1.320.2361390.2776926
1.32-1.340.2402470.2515953
1.34-1.360.2615370.2533961
1.36-1.380.3133490.2643957
1.38-1.410.2985560.2654942
1.41-1.430.2553550.2654974
1.43-1.460.2635650.2452946
1.46-1.490.2828520.2423983
1.49-1.530.2886460.2439984
1.53-1.570.283530.2562984
1.57-1.610.2292620.2354954
1.61-1.660.2576470.26111006
1.66-1.710.2135460.2458993
1.71-1.770.3707480.2461984
1.77-1.840.2335580.2192992
1.84-1.930.2834510.21251013
1.93-2.030.2166520.22341015
2.03-2.160.2146630.21731008
2.16-2.320.1782580.2068991
2.32-2.560.2481570.19851019
2.56-2.930.2674480.2191042
2.93-3.690.2021560.20341037
3.69-650.2284474.50.222144011100
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 DIFFRACTION4ro0503918.prxro0503918.tpx

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