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- PDB-4ipf: The 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337 -

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Basic information

Entry
Database: PDB / ID: 4ipf
TitleThe 1.7A crystal structure of humanized Xenopus MDM2 with RO5045337
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/ANTAGONIST / MDM2 / P53 / PROTEIN-PROTEIN INTERACTION / IMIDAZOLINE / E3 UBIQUITIN LIGASE / NUCLEUS / LIGASE-ANTAGONIST complex
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-1F0 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.7 Å
AuthorsGraves, B.J. / Lukacs, C. / Kammlott, R.U. / Crowther, R.
Citation
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.
#1: 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
DepositionJan 9, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 20, 2013Provider: repository / Type: Initial release
Revision 1.1Apr 24, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Structure summary
Category: chem_comp / chem_comp_atom ...chem_comp / chem_comp_atom / chem_comp_bond / database_2 / struct_ref_seq_dif / struct_site
Item: _chem_comp.pdbx_synonyms / _database_2.pdbx_DOI ..._chem_comp.pdbx_synonyms / _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)10,7514
Polymers9,8311
Non-polymers9203
Water2,468137
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)43.083, 67.493, 66.724
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-383-

HOH

DetailsTHE FULL-LENGTH PROTEIN WOULD FORM A DIMER THROUGH ITS C-TERMINAL DOMAIN BUT THIS N-TERMINAL DOMAIN FORMS ONLY MONOMERS.

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Components

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


Mass: 9831.419 Da / Num. of mol.: 1 / Fragment: 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-1F0 / [(4S,5R)-2-(4-tert-butyl-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dimethyl-4,5-dihydro-1H-imidazol-1-yl]{4-[3-(methylsulfonyl)propyl]piperazin-1-yl}methanone / RO5045337 / RG7112


Mass: 727.783 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C38H48Cl2N4O4S
#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.: 137 / 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: 2.47 Å3/Da / Density % sol: 50.14 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6.5
Details: 50% SATURATED AMMONIUM SULFATE, 100 mM BIS-TRIS, pH 6.5, 5% (V/V) PEG200, 5 mM DTT, VAPOR DIFFUSION, HANGING DROP, temperature 278.0K

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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: Jan 23, 2006
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.55→36.3 Å / Num. all: 14473 / Num. obs: 11957 / % possible obs: 82.6 % / Observed criterion σ(F): 0 / Observed criterion σ(I): 0 / Redundancy: 3.58 % / Biso Wilson estimate: 23.8 Å2 / Rmerge(I) obs: 0.037 / Net I/σ(I): 20.3
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. unique allDiffraction-ID% possible all
1.55-1.611.990.1693.3290120.5
3.34-36.313.730.02248.51527199.2
2.65-3.343.860.03430.51470199.9
2.32-2.653.860.0392514651100
2.1-2.323.810.05318.21422199.6
1.95-2.13.760.0812.81450199.7
1.84-1.953.70.1049.414241100
1.75-1.843.570.1167.61347194.1
1.67-1.752.90.136942166.4
1.61-1.672.40.1514.4620143.5

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
CNX2005refinement
d*TREKdata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.7→33.75 Å / Rfactor Rfree error: 0.01 / Data cutoff high absF: 850326.78 / 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
Rfree0.229 548 5.1 %RANDOM
Rwork0.208 ---
all0.209 10703 --
obs0.209 10703 96.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 48.5667 Å2 / ksol: 0.373979 e/Å3
Displacement parametersBiso mean: 16.9 Å2
Baniso -1Baniso -2Baniso -3
1--0.64 Å20 Å20 Å2
2--2.63 Å20 Å2
3----1.99 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.24 Å0.21 Å
Luzzati d res low-5 Å
Luzzati sigma a0.09 Å0.07 Å
Refinement stepCycle: LAST / Resolution: 1.7→33.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms690 0 59 137 886
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.004
X-RAY DIFFRACTIONc_angle_deg1.4
X-RAY DIFFRACTIONc_dihedral_angle_d21
X-RAY DIFFRACTIONc_improper_angle_d1.94
X-RAY DIFFRACTIONc_mcbond_it1.11.5
X-RAY DIFFRACTIONc_mcangle_it1.672
X-RAY DIFFRACTIONc_scbond_it1.972
X-RAY DIFFRACTIONc_scangle_it2.832.5
LS refinement shellResolution: 1.7→1.81 Å / Rfactor Rfree error: 0.044 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.389 78 5.2 %
Rwork0.338 1417 -
obs--82.7 %
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 DIFFRACTION4RO5045337.prxRO5045337.tpx

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