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- PDB-4ogv: Co-Crystal Structure of MDM2 with Inhibitor Compound 49 -

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Basic information

Entry
Database: PDB / ID: 4ogv
TitleCo-Crystal Structure of MDM2 with Inhibitor Compound 49
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / P53 / protein-protein interaction / ligase-ligase inhibitor complex
Function / homology
Function and homology information


cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / response to ether / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of signal transduction by p53 class mediator / fibroblast activation / atrial septum development / receptor serine/threonine kinase binding ...cellular response to vitamin B1 / response to formaldehyde / response to water-immersion restraint stress / traversing start control point of mitotic cell cycle / response to ether / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / negative regulation of signal transduction by p53 class mediator / fibroblast activation / atrial septum development / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / positive regulation of vascular associated smooth muscle cell migration / peroxisome proliferator activated receptor binding / SUMO transferase activity / negative regulation of protein processing / response to iron ion / response to steroid hormone / NEDD8 ligase activity / cellular response to peptide hormone stimulus / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / response to magnesium ion / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / protein sumoylation / protein localization to nucleus / blood vessel remodeling / cellular response to UV-C / cellular response to estrogen stimulus / protein autoubiquitination / cellular response to actinomycin D / ribonucleoprotein complex binding / positive regulation of vascular associated smooth muscle cell proliferation / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / positive regulation of mitotic cell cycle / positive regulation of protein export from nucleus / response to cocaine / proteolysis involved in protein catabolic process / ubiquitin binding / Stabilization of p53 / protein destabilization / Regulation of RUNX3 expression and activity / establishment of protein localization / RING-type E3 ubiquitin transferase / cellular response to growth factor stimulus / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / endocytic vesicle membrane / ubiquitin protein ligase activity / p53 binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / negative regulation of neuron projection development / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / proteasome-mediated ubiquitin-dependent protein catabolic process / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / regulation of cell cycle / Ub-specific processing proteases / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm
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-2U7 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.197 Å
AuthorsShaffer, P.L. / Huang, X. / Yakowec, P. / Long, A.M.
CitationJournal: J.Med.Chem. / Year: 2014
Title: Novel Inhibitors of the MDM2-p53 Interaction Featuring Hydrogen Bond Acceptors as Carboxylic Acid Isosteres.
Authors: Gonzalez, A.Z. / Li, Z. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Duquette, J. / Eksterowicz, J. / Fox, B.M. / Fu, J. / Huang, X. / Houze, J. / Jin, L. / Li, Y. / Ling, Y. / Lo, M.C. ...Authors: Gonzalez, A.Z. / Li, Z. / Beck, H.P. / Canon, J. / Chen, A. / Chow, D. / Duquette, J. / Eksterowicz, J. / Fox, B.M. / Fu, J. / Huang, X. / Houze, J. / Jin, L. / Li, Y. / Ling, Y. / Lo, M.C. / Long, A.M. / McGee, L.R. / McIntosh, J. / Oliner, J.D. / Osgood, T. / Rew, Y. / Saiki, A.Y. / Shaffer, P. / Wortman, S. / Yakowec, P. / Yan, X. / Ye, Q. / Yu, D. / Zhao, X. / Zhou, J. / Olson, S.H. / Sun, D. / Medina, J.C.
History
DepositionJan 16, 2014Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 2, 2014Provider: repository / Type: Initial release
Revision 1.1Jun 18, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _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
B: E3 ubiquitin-protein ligase Mdm2
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,9666
Polymers33,2973
Non-polymers1,6693
Water57632
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6552
Polymers11,0991
Non-polymers5561
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)11,6552
Polymers11,0991
Non-polymers5561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
3
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6552
Polymers11,0991
Non-polymers5561
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)56.301, 97.412, 105.129
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-605-

HOH

Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B
31C

NCS domain segments:
Dom-IDComponent-IDEns-IDRefine codeAuth asym-IDAuth seq-ID
1112A1 - 500
2112B1 - 500
3112C1 - 500

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Components

#1: Protein E3 ubiquitin-protein ligase Mdm2 / Double minute 2 protein / Hdm2 / Oncoprotein Mdm2 / p53-binding protein Mdm2


Mass: 11099.000 Da / Num. of mol.: 3 / Fragment: UNP Residues 7-111
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-2U7 / [(2S,5R,6R)-4-[(2S)-1-(tert-butylsulfonyl)butan-2-yl]-6-(3-chlorophenyl)-5-(4-chlorophenyl)-3-oxomorpholin-2-yl]acetic acid


Mass: 556.498 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: C26H31Cl2NO6S
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 32 / 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: 2.16 Å3/Da / Density % sol: 43.17 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 5
Details: 1.6-2.3M Ammonium Sulfate, 0.1M sodium citrate, pH 5.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Oct 27, 2011
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.197→50 Å / Num. obs: 15041 / % possible obs: 99.9 % / Redundancy: 7 % / Rmerge(I) obs: 0.082 / Χ2: 1.537 / Net I/σ(I): 11
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique allΧ2Diffraction-ID% possible all
2.197-2.286.20.78414800.79199.9
2.28-2.376.90.59914790.7881100
2.37-2.487.30.47214710.8121100
2.48-2.617.30.34314860.861100
2.61-2.777.30.23714820.951100
2.77-2.997.30.16415071.2091100
2.99-3.297.20.10314871.567199.9
3.29-3.7670.07615262.461100
3.76-4.746.70.05615143.19199.9
4.74-506.50.04216092.759199.8

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Processing

Software
NameVersionClassificationNB
SCALEPACKdata scaling
REFMAC5.5.0109refinement
PDB_EXTRACT3.14data extraction
HKL-2000data reduction
HKL-2000data scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB Entry 4ERF

4erf


Resolution: 2.197→48.74 Å / Cor.coef. Fo:Fc: 0.923 / Cor.coef. Fo:Fc free: 0.914 / Occupancy max: 1 / Occupancy min: 0.5 / SU B: 10.45 / SU ML: 0.213 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.378 / ESU R Free: 0.253 / Stereochemistry target values: MAXIMUM LIKELIHOOD
RfactorNum. reflection% reflectionSelection details
Rfree0.2835 747 5 %RANDOM
Rwork0.256 ---
obs0.2573 14956 98.97 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso max: 74.29 Å2 / Biso mean: 45.268 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1--0.81 Å20 Å20 Å2
2---0.67 Å20 Å2
3---1.48 Å2
Refinement stepCycle: LAST / Resolution: 2.197→48.74 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2115 0 108 32 2255
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222271
X-RAY DIFFRACTIONr_angle_refined_deg1.1882.0573096
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0275261
X-RAY DIFFRACTIONr_dihedral_angle_2_deg42.99824.07481
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.36615381
X-RAY DIFFRACTIONr_dihedral_angle_4_deg4.962156
X-RAY DIFFRACTIONr_chiral_restr0.0770.2369
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.0211623
X-RAY DIFFRACTIONr_mcbond_it0.9091.51329
X-RAY DIFFRACTIONr_mcangle_it1.32422154
X-RAY DIFFRACTIONr_scbond_it2.6593942
X-RAY DIFFRACTIONr_scangle_it3.9144.5942
Refine LS restraints NCS

Ens-ID: 1 / Refine-ID: X-RAY DIFFRACTION

Dom-IDAuth asym-IDNumberTypeRms dev position (Å)Weight position
1A356TIGHT POSITIONAL0.020.05
2B356TIGHT POSITIONAL0.020.05
3C356TIGHT POSITIONAL0.020.05
1A349MEDIUM POSITIONAL0.020.5
2B349MEDIUM POSITIONAL0.020.5
3C349MEDIUM POSITIONAL0.020.5
1A356TIGHT THERMAL0.10.5
2B356TIGHT THERMAL0.110.5
3C356TIGHT THERMAL0.20.5
1A349MEDIUM THERMAL0.092
2B349MEDIUM THERMAL0.092
3C349MEDIUM THERMAL0.162
LS refinement shellResolution: 2.197→2.254 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.379 54 -
Rwork0.338 966 -
all-1020 -
obs--91.81 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
16.22141.2187-1.34843.9326-0.48383.79740.14220.1305-0.4007-0.286-0.2744-0.505-0.2625-0.11960.13210.05820.03350.03810.03120.02220.090413.09377.2784-32.3737
25.83251.8254-0.80714.2903-0.65623.9544-0.2158-0.0807-0.65250.39270.0864-0.1307-0.2215-0.22590.12940.07770.02950.03670.01810.01090.092229.335916.6945-2.6687
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A18 - 501
2X-RAY DIFFRACTION2B18 - 501

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