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- PDB-4jsc: The 2.5A crystal structure of humanized Xenopus MDM2 with RO53165... -

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Basic information

Entry
Database: PDB / ID: 4jsc
TitleThe 2.5A crystal structure of humanized Xenopus MDM2 with RO5316533 - a pyrrolidine MDM2 inhibitor
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / pyrrolidine / ligase-antagonist complex / E3 ubiquitin ligase / p53 / nucleus / LIGASE-LIGASE INHIBITOR 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 / protein ubiquitination / regulation of cell cycle / cell cycle / apoptotic process / nucleolus ...regulation of biological quality / RING-type E3 ubiquitin transferase / ubiquitin protein ligase activity / p53 binding / regulation of gene expression / protein ubiquitination / regulation of cell cycle / cell cycle / apoptotic process / nucleolus / negative regulation of apoptotic process / nucleoplasm / identical protein binding / metal ion binding / nucleus / 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-1OY / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesXenopus laevis (African clawed frog)
MethodX-RAY DIFFRACTION / MOLECULAR REPLACEMENT / Resolution: 2.5 Å
AuthorsJanson, C.A. / Lukacs, C. / Graves, B.
Citation
Journal: J.Med.Chem. / Year: 2013
Title: Discovery of RG7388, a Potent and Selective p53-MDM2 Inhibitor in Clinical Development.
Authors: Ding, Q. / Zhang, Z. / Liu, J.J. / Jiang, N. / Zhang, J. / Ross, T.M. / Chu, X.J. / Bartkovitz, D. / Podlaski, F. / Janson, C. / Tovar, C. / Filipovic, Z.M. / Higgins, B. / Glenn, K. / ...Authors: Ding, Q. / Zhang, Z. / Liu, J.J. / Jiang, N. / Zhang, J. / Ross, T.M. / Chu, X.J. / Bartkovitz, D. / Podlaski, F. / Janson, C. / Tovar, C. / Filipovic, Z.M. / Higgins, B. / Glenn, K. / Packman, K. / Vassilev, L.T. / 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.
History
DepositionMar 22, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 24, 2013Provider: repository / Type: Initial release
Revision 1.1Feb 5, 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
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)21,0344
Polymers19,9252
Non-polymers1,1092
Water93752
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,5172
Polymers9,9631
Non-polymers5541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)10,5172
Polymers9,9631
Non-polymers5541
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.490, 73.720, 40.968
Angle α, β, γ (deg.)90.00, 108.44, 90.00
Int Tables number5
Space group name H-MC121
DetailsFULL-LENGTH PROTEIN IS A DIMER, FORMED THROUGH CONTACTS IN THE C-TERMINAL DOMAINS, BUT THE N-TERMINAL FRAGMENT IS A MONOMER ON ITS OWN

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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.: 2 / 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-1OY / (3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-N-[(3S)-3,4-dihydroxybutyl]-5-(2,2-dimethylpropyl)-D-prolinamide


Mass: 554.456 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C27H31Cl2F2N3O3
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 52 / 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: 2.71 Å3/Da / Density % sol: 54.67 %
Crystal growTemperature: 278 K / Method: vapor diffusion, hanging drop / pH: 6
Details: 50% SATURATED AMMONIUM SULFATE, 0.1M BIS-TRIS, PH 6.0, 5% PEG 550MME, 5mM DTT, VAPOR DIFFUSION, HANGING DROP, temperature 278K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU MICROMAX-007 / Wavelength: 1.5418 Å
DetectorType: RIGAKU RAXIS HTC / Detector: IMAGE PLATE / Date: Dec 10, 2008 / Details: MIRRORS
RadiationMonochromator: MIRRORS / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.5418 Å / Relative weight: 1
ReflectionResolution: 2.4→35.81 Å / Num. all: 8382 / Num. obs: 8382 / % possible obs: 99.9 % / Observed criterion σ(I): 0 / Redundancy: 3.56 % / Biso Wilson estimate: 37.8 Å2 / Rmerge(I) obs: 0.121 / Net I/σ(I): 5.9
Reflection shellResolution: 2.4→2.49 Å / Redundancy: 3.61 % / Rmerge(I) obs: 0.429 / Mean I/σ(I) obs: 1.8 / Num. unique all: 824 / % possible all: 100

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Processing

Software
NameVersionClassification
CrystalCleardata collection
MOLREPphasing
CNX2005refinement
CrystalCleardata reduction
d*TREKdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.5→35.81 Å / Rfactor Rfree error: 0.019 / Data cutoff high absF: 713583.85 / 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
Rfree0.37 393 5.3 %RANDOM
Rwork0.312 ---
all0.316 7443 --
obs0.316 7443 99.9 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 45.8811 Å2 / ksol: 0.380777 e/Å3
Displacement parametersBiso mean: 42 Å2
Baniso -1Baniso -2Baniso -3
1-0 Å20 Å20 Å2
2--0 Å20 Å2
3---0 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.69 Å0.54 Å
Luzzati d res low-5 Å
Luzzati sigma a0.56 Å0.44 Å
Refinement stepCycle: LAST / Resolution: 2.5→35.81 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1348 0 74 52 1474
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.008
X-RAY DIFFRACTIONc_angle_deg1.2
X-RAY DIFFRACTIONc_dihedral_angle_d24.4
X-RAY DIFFRACTIONc_improper_angle_d0.87
X-RAY DIFFRACTIONc_mcbond_it1.571.5
X-RAY DIFFRACTIONc_mcangle_it2.652
X-RAY DIFFRACTIONc_scbond_it1.992
X-RAY DIFFRACTIONc_scangle_it32.5
Refine LS restraints NCSNCS model details: NONE
LS refinement shellResolution: 2.5→2.66 Å / Rfactor Rfree error: 0.064 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.514 64 5.2 %
Rwork0.404 1178 -
obs-1237 100 %
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 DIFFRACTION4RO5316533.prxRO5316533.tpx

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