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- PDB-5j7f: Structure of MDM2 with low molecular weight inhibitor with alipha... -

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Basic information

Entry
Database: PDB / ID: 5j7f
TitleStructure of MDM2 with low molecular weight inhibitor with aliphatic linker.
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / p53 / MDM2 / MDMX / protein-protein interaction / cancer / 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 / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / 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 / proteolysis involved in protein catabolic process / ubiquitin binding / response to cocaine / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / establishment of protein localization / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / cellular response to gamma radiation / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / response to toxic substance / 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-6GG / 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. / Kubica, K. / Guzik, K. / Dubin, G. / Holak, T.A.
Funding support Netherlands, Poland, 5items
OrganizationGrant numberCountry
National Institutes of Health1R21GM087617, 1R01GM097082, 1P41GM094055 Netherlands
National Science CentreUMO-2014/12/W/NZ1/00457 Poland
National Science CentreUMO-2011/01/D/NZ1/01169 Poland
National Science CentreUMO-2015/17/N/NZ1/00025 Poland
Foundation for Polish ScienceTEAM/2011-8/2 Poland
CitationJournal: J. Med. Chem. / Year: 2017
Title: 1,4,5-Trisubstituted Imidazole-Based p53-MDM2/MDMX Antagonists with Aliphatic Linkers for Conjugation with Biological Carriers.
Authors: Twarda-Clapa, A. / Krzanik, S. / Kubica, K. / Guzik, K. / Labuzek, B. / Neochoritis, C.G. / Khoury, K. / Kowalska, K. / Czub, M. / Dubin, G. / Domling, A. / Skalniak, L. / Holak, T.A.
History
DepositionApr 6, 2016Deposition site: RCSB / Processing site: PDBE
Revision 1.0May 17, 2017Provider: repository / Type: Initial release
Revision 1.1Jun 7, 2017Group: Database references
Revision 1.2Jan 31, 2018Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.3Jan 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
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)59,3558
Polymers56,6374
Non-polymers2,7184
Water2,612145
1
A: E3 ubiquitin-protein ligase Mdm2
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,6774
Polymers28,3182
Non-polymers1,3592
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)29,6774
Polymers28,3182
Non-polymers1,3592
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)37.758, 174.750, 37.810
Angle α, β, γ (deg.)90.000, 93.480, 90.000
Int Tables number4
Space group name H-MP1211

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Components

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


Mass: 14159.176 Da / Num. of mol.: 4
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-6GG / 4-({6-[(6-chloro-3-{1-[(4-chlorophenyl)methyl]-4-(4-fluorophenyl)-1H-imidazol-5-yl}-1H-indole-2-carbonyl)oxy]hexyl}amino)-4-oxobutanoic acid


Mass: 679.565 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C35H33Cl2FN4O5
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 145 / 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: 2.2 Å3/Da / Density % sol: 44.05 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M HEPES pH 7.5 with 0.2 M NaCl and 25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.9184 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 10, 2016
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9184 Å / Relative weight: 1
ReflectionResolution: 2.004→87.38 Å / Num. obs: 32584 / % possible obs: 99.7 % / Redundancy: 3.4 % / Rsym value: 0.089 / Net I/av σ(I): 8.25 / Net I/σ(I): 10.8
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
2.004-2.113.30.9520.8199.1
2.11-2.243.50.6431.2199.8
2.24-2.43.40.4321.8199.7
2.4-2.593.30.2792.8199.9
2.59-2.833.60.1964199.9
2.83-3.173.40.1117199.9
3.17-3.663.50.05613.5199.8
3.66-4.483.50.03421.2199.7
4.48-6.343.40.02923.6199.8
6.34-37.743.30.02127198.6

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.34 Å37.74 Å
Translation3.34 Å37.74 Å

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Processing

Software
NameVersionClassification
SCALA3.3.21data scaling
PHASER2.5.5phasing
REFMAC5.8.0049refinement
PDB_EXTRACT3.2data extraction
XDSdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HBM

4hbm


Resolution: 2→87.38 Å / Cor.coef. Fo:Fc: 0.968 / Cor.coef. Fo:Fc free: 0.938 / SU B: 12.358 / SU ML: 0.17 / SU R Cruickshank DPI: 0.1724 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.172 / ESU R Free: 0.168 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2423 1647 5.1 %RANDOM
Rwork0.183 ---
obs0.186 30895 99.65 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 110.12 Å2 / Biso mean: 40.523 Å2 / Biso min: 19.44 Å2
Baniso -1Baniso -2Baniso -3
1-0.9 Å20 Å20.41 Å2
2---1.55 Å2-0 Å2
3---0.59 Å2
Refinement stepCycle: final / Resolution: 2→87.38 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3221 0 188 145 3554
Biso mean--36.44 45.7 -
Num. residues----404
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0160.0193485
X-RAY DIFFRACTIONr_bond_other_d0.0020.023358
X-RAY DIFFRACTIONr_angle_refined_deg2.1512.0474722
X-RAY DIFFRACTIONr_angle_other_deg0.89237713
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0925400
X-RAY DIFFRACTIONr_dihedral_angle_2_deg44.57124.03134
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.31915602
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.5311516
X-RAY DIFFRACTIONr_chiral_restr0.1020.2523
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0213804
X-RAY DIFFRACTIONr_gen_planes_other0.0030.02780
X-RAY DIFFRACTIONr_mcbond_it1.8082.3051612
X-RAY DIFFRACTIONr_mcbond_other1.8092.3031611
X-RAY DIFFRACTIONr_mcangle_it2.7343.4362008
LS refinement shellResolution: 2.004→2.056 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.331 143 -
Rwork0.302 2220 -
all-2363 -
obs--98.79 %
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)
11.2394-0.3851-0.31471.8107-0.07081.8297-0.01540.004-0.0778-0.02510.03340.035-0.0189-0.1041-0.0180.1545-0.02630.00490.01160.01120.272738.71130.669844.9125
21.12-0.59230.43763.0157-0.15231.9169-0.0098-0.1279-0.03660.0067-0.0459-0.1211-0.13820.10260.05570.0634-0.0109-0.00280.03340.02210.313948.8524-20.560350.8723
31.60680.4060.2042.97130.79681.37790.0141-0.09320.04350.1606-0.0285-0.00420.16510.02860.01440.11020.00950.00890.00990.02740.326362.0385-42.778152.8111
41.68810.23750.1212.3204-0.58170.98210.0084-0.05140.11910.1145-0.02270.04920.0431-0.0720.01430.2025-0.02410.03410.0098-0.01580.25541.858221.952832.1997
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A11 - 111
2X-RAY DIFFRACTION2B12 - 114
3X-RAY DIFFRACTION3C11 - 111
4X-RAY DIFFRACTION4D12 - 110

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