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- PDB-4zgk: Structure of Mdm2 with low molecular weight inhibitor. -

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Basic information

Entry
Database: PDB / ID: 4zgk
TitleStructure of Mdm2 with low molecular weight inhibitor.
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / p53-Mdm2/MdmX interaction / inhibitor
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 / regulation of protein catabolic process / blood vessel development / 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 / cellular response to UV-C / blood vessel remodeling / 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 / ubiquitin binding / proteolysis involved in protein catabolic process / response to cocaine / 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 / ubiquitin protein ligase binding / positive regulation of cell population proliferation / 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-4NX / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2 Å
AuthorsTwarda-Clapa, A. / Zak, K.M. / Wrona, E.M. / Grudnik, P. / Dubin, G. / Holak, T.A.
Funding support Poland, 2items
OrganizationGrant numberCountry
Foundation for Polish ScienceTEAM/2011-8/2 Poland
National Centre of ScienceUMO-2011/01/D/NZ1/01169 Poland
CitationJournal: ACS Chem. Biol. / Year: 2016
Title: A Unique Mdm2-Binding Mode of the 3-Pyrrolin-2-one- and 2-Furanone-Based Antagonists of the p53-Mdm2 Interaction.
Authors: Surmiak, E. / Twarda-Clapa, A. / Zak, K.M. / Musielak, B. / Tomala, M.D. / Kubica, K. / Grudnik, P. / Madej, M. / Jablonski, M. / Potempa, J. / Kalinowska-Tluscik, J. / Domling, A. / Dubin, G. / Holak, T.A.
History
DepositionApr 23, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Oct 19, 2016Provider: repository / Type: Initial release
Revision 1.1Dec 28, 2016Group: Database references
Revision 1.2Jan 10, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_ncs_dom_lim
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)24,0554
Polymers23,0572
Non-polymers9982
Water2,054114
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,0272
Polymers11,5281
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,0272
Polymers11,5281
Non-polymers4991
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)36.610, 56.550, 97.310
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21B

NCS domain segments:

Component-ID: _ / Ens-ID: 1 / Beg auth comp-ID: GLN / Beg label comp-ID: GLN / End auth comp-ID: VAL / End label comp-ID: VAL / Refine code: _ / Auth seq-ID: 18 - 109 / Label seq-ID: 2 - 93

Dom-IDAuth asym-IDLabel asym-ID
1AA
2BB

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Components

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


Mass: 11528.488 Da / Num. of mol.: 2 / Fragment: UNP residues 18-114
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli BL21 (bacteria)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Chemical ChemComp-4NX / (5R)-3,5-bis(4-chlorobenzyl)-4-(6-chloro-1H-indol-3-yl)-5-hydroxyfuran-2(5H)-one


Mass: 498.785 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C26H18Cl3NO3
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 114 / 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: 2.21 Å3/Da / Density % sol: 44.38 %
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / Details: 0.1 M HEPES pH 7.5 containing 30% PEG 1000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID23-2 / Wavelength: 0.873 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Nov 27, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.873 Å / Relative weight: 1
ReflectionResolution: 1.739→48.893 Å / Num. all: 11908 / Num. obs: 11908 / % possible obs: 84.8 % / Redundancy: 3.9 % / Rpim(I) all: 0.071 / Rrim(I) all: 0.151 / Rsym value: 0.132 / Net I/av σ(I): 3.5 / Net I/σ(I): 6.3 / Num. measured all: 46290
Reflection shell

Diffraction-ID: 1 / Rejects: _

Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsNum. measured allNum. unique allRpim(I) allRsym valueNet I/σ(I) obs% possible all
2-2.113.50.3222.3623217560.1860.3223.486.8
2.11-2.243.70.292.5607716390.1610.293.986.5
2.24-2.394.10.2941.9632215530.1590.2944.486.2
2.39-2.584.10.2213.2605114610.1160.2215.286.3
2.58-2.833.90.1833.7522313260.0980.1835.985.2
2.83-3.163.70.1285429311690.0730.1287.483.7
3.16-3.6540.1035.9424510490.0540.1039.683.3
3.65-4.474.20.0896.336888800.0460.08911.581.8
4.47-6.323.80.0916.525636820.0510.0911179.9
6.32-29.3054.10.0964.315963930.0470.09611.478.9

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.88 Å29.31 Å
Translation3.88 Å29.31 Å

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Processing

Software
NameVersionClassification
MOSFLM7.0.9data reduction
SCALA3.3.21data scaling
PHASER2.5.5phasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.15data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TJ2

3tj2


Resolution: 2→30 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.908 / WRfactor Rfree: 0.2466 / WRfactor Rwork: 0.1874 / FOM work R set: 0.8231 / SU B: 9.92 / SU ML: 0.151 / SU R Cruickshank DPI: 0.2619 / SU Rfree: 0.211 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.262 / ESU R Free: 0.211 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.247 600 5 %RANDOM
Rwork0.1881 ---
obs0.191 11285 83.29 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 65.13 Å2 / Biso mean: 26.686 Å2 / Biso min: 9.71 Å2
Baniso -1Baniso -2Baniso -3
1-2.27 Å20 Å2-0 Å2
2--0.63 Å2-0 Å2
3----2.89 Å2
Refinement stepCycle: final / Resolution: 2→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1562 0 66 114 1742
Biso mean--20.51 27.99 -
Num. residues----191
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0130.0191687
X-RAY DIFFRACTIONr_bond_other_d0.0050.021651
X-RAY DIFFRACTIONr_angle_refined_deg1.8742.0422288
X-RAY DIFFRACTIONr_angle_other_deg1.24733799
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9565195
X-RAY DIFFRACTIONr_dihedral_angle_2_deg45.26524.11868
X-RAY DIFFRACTIONr_dihedral_angle_3_deg19.81115319
X-RAY DIFFRACTIONr_dihedral_angle_4_deg11.821158
X-RAY DIFFRACTIONr_chiral_restr0.1030.2251
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.0211835
X-RAY DIFFRACTIONr_gen_planes_other0.0040.02379
X-RAY DIFFRACTIONr_mcbond_it1.2411.853771
X-RAY DIFFRACTIONr_mcbond_other1.2221.85770
X-RAY DIFFRACTIONr_mcangle_it1.8922.76963
Refine LS restraints NCS

Ens-ID: 1 / Number: 5464 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.15 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2B
LS refinement shellResolution: 2→2.052 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.292 48 -
Rwork0.277 840 -
all-888 -
obs--85.38 %
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)
10.30690.3950.1780.59520.37364.2051-0.030.00280.0036-0.02220.017-0.0340.19760.17660.0130.02770.0035-0.00710.01340.00350.03039.5938-3.9201-22.0759
21.2204-0.0615-0.78980.88630.07313.19780.0130.0469-0.0409-0.0359-0.0272-0.02940.0644-0.22530.01430.0071-0.01140.00150.0336-0.01080.08242.0244-1.2072-44.759
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A17 - 110
2X-RAY DIFFRACTION2B18 - 114

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