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- PDB-4j7d: The 1.25A crystal structure of humanized Xenopus MDM2 with a nutl... -

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Basic information

Entry
Database: PDB / ID: 4j7d
TitleThe 1.25A crystal structure of humanized Xenopus MDM2 with a nutlin fragment, RO5045331
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/ANTAGONIST / PROTEIN-PROTEIN INTERACTION / E3 UBIQUITIN LIGASE / LIGASE-ANTAGONIST COMPLEX / P53 / IMIDAZOLINE / 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-I31 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.25 Å
AuthorsJanson, C. / Lukacs, C. / 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 / 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. / Higgins, B. / Xia, M. / Tardell, C. / Garrido, R. / Lee, E. / Kolinsky, K. / To, K.-H. / Linn, M. / Podlaski, F. / Wovkulich, P. / Vu, B. / Vassilev, L.T.
#2: Journal: To be Published
Title: Discovery of RG7112: a small-molecule mdm2 antagonist 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. / Thompson, T. / Packman, K. / Vassilev, L. / Graves, B.
#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 13, 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

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)10,6504
Polymers9,9631
Non-polymers6883
Water2,252125
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)31.639, 38.158, 69.027
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121
DetailsN-TERMINAL FRAGMENT EXISTS AS A MONOMER BUT FULL-LENGTH PROTEIN WOULD BE A DIMER

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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-I31 / (4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazole


Mass: 495.483 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H32Cl2N2O
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 125 / 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: 2.09 Å3/Da / Density % sol: 41.18 %
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 278K

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Data collection

DiffractionMean temperature: 80 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: Sep 22, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.17→40 Å / Num. all: 28271 / Num. obs: 27483 / % possible obs: 98.2 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 6.1 % / Biso Wilson estimate: 10.8 Å2 / Rmerge(I) obs: 0.044 / Net I/σ(I): 9.9
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
1.17-1.245.20.47123696190.1
3.71-405.50.02821.71036199.5
2.62-3.716.20.02723.81729199.9
2.14-2.6260.03421.42203199.9
1.85-2.146.40.0419.22576199.9
1.66-1.856.20.06213.92879199.9
1.51-1.666.50.099.73192199.9
1.4-1.516.10.155.93453199.7
1.31-1.46.40.22543628199.4
1.24-1.315.90.362.53879198.7

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Processing

Software
NameVersionClassification
HKL-3000data collection
MOLREPphasing
CNX2005refinement
HKL-3000data reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.25→34.51 Å / Rfactor Rfree error: 0.007 / Data cutoff high absF: 902998.51 / 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
Rfree0.224 1183 5 %RANDOM
Rwork0.192 ---
all0.194 23656 --
obs0.194 23656 99.3 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 34.4755 Å2 / ksol: 0.340739 e/Å3
Displacement parametersBiso mean: 14.9 Å2
Baniso -1Baniso -2Baniso -3
1-1.06 Å20 Å20 Å2
2--0.42 Å20 Å2
3----1.48 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.15 Å0.13 Å
Luzzati d res low-5 Å
Luzzati sigma a0.04 Å0.07 Å
Refinement stepCycle: LAST / Resolution: 1.25→34.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms698 0 44 125 867
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.003
X-RAY DIFFRACTIONc_angle_deg1
X-RAY DIFFRACTIONc_dihedral_angle_d20.4
X-RAY DIFFRACTIONc_improper_angle_d0.75
X-RAY DIFFRACTIONc_mcbond_it1.041.5
X-RAY DIFFRACTIONc_mcangle_it1.562
X-RAY DIFFRACTIONc_scbond_it2.262
X-RAY DIFFRACTIONc_scangle_it3.142.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 1.25→1.33 Å / Rfactor Rfree error: 0.018 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.253 193 5.1 %
Rwork0.214 3622 -
obs--97.8 %
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 DIFFRACTION4ro5045331.prxro5045331.tpx

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