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- PDB-5j7g: Structure of MDM2 with low molecular weight inhibitor with alipha... -

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Basic information

Entry
Database: PDB / ID: 5j7g
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 / response to ether / traversing start control point of mitotic cell cycle / 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 / response to ether / traversing start control point of mitotic cell cycle / 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 / response to iron ion / negative regulation of protein processing / response to steroid hormone / SUMO transferase activity / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / cellular response to alkaloid / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / protein sumoylation / ligase activity / SUMOylation of transcription factors / protein localization to nucleus / cellular response to actinomycin D / cellular response to UV-C / protein autoubiquitination / blood vessel remodeling / cellular response to estrogen stimulus / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / positive regulation of vascular associated smooth muscle cell proliferation / transcription repressor complex / NPAS4 regulates expression of target genes / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / response to cocaine / positive regulation of protein export from nucleus / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / cellular response to gamma radiation / RING-type E3 ubiquitin transferase / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Regulation of TP53 Degradation / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / ubiquitin-dependent protein catabolic process / cellular response to hypoxia / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / protein ubiquitination / regulation of cell cycle / Ub-specific processing proteases / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / ubiquitin protein ligase binding / positive regulation of cell population proliferation / positive regulation of gene expression / nucleolus / negative regulation of apoptotic process / negative regulation of transcription by RNA polymerase II / enzyme binding / protein-containing complex / zinc ion binding / nucleoplasm / identical protein binding
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: 1.85 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)53,0368
Polymers50,3184
Non-polymers2,7184
Water1,53185
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules

D: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,5184
Polymers25,1592
Non-polymers1,3592
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation2_565x,-y+1,-z1
Buried area900 Å2
ΔGint-7 kcal/mol
Surface area10490 Å2
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,5184
Polymers25,1592
Non-polymers1,3592
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1140 Å2
ΔGint-8 kcal/mol
Surface area10650 Å2
MethodPISA
3
D: E3 ubiquitin-protein ligase Mdm2
hetero molecules

C: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)26,5184
Polymers25,1592
Non-polymers1,3592
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation3_854-x+3,y+1/2,-z-1/21
Buried area900 Å2
ΔGint-7 kcal/mol
Surface area10490 Å2
MethodPISA
Unit cell
Length a, b, c (Å)36.750, 74.301, 171.400
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number18
Space group name H-MP22121

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Components

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


Mass: 12579.468 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 / Water


Mass: 18.015 Da / Num. of mol.: 85 / 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: 2.33 Å3/Da / Density % sol: 47.11 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 0.1 M Na HEPES pH 7.5 with 10% isopropanol and 20% PEG 4000

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 24, 2015
RadiationMonochromator: Double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.85→85.7 Å / Num. obs: 40453 / % possible obs: 98.7 % / Redundancy: 3.9 % / Rsym value: 0.061 / Net I/av σ(I): 3.254 / Net I/σ(I): 10
Reflection shell
Resolution (Å)Redundancy (%)Rmerge(I) obsMean I/σ(I) obsDiffraction-ID% possible all
1.85-1.953.80.5091.5198.7
1.95-2.073.90.2792.6197.7
2.07-2.214.10.1833.8199.2
2.21-2.393.70.1284.9199.1
2.39-2.6240.0955.9198.6
2.62-2.9340.0747.5198.8
2.93-3.383.80.05710199.1
3.38-4.1440.04910.6199.4
4.14-5.853.70.04810.4198.8
5.85-28.5373.60.0554.5197.1

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Phasing

PhasingMethod: molecular replacement
Phasing MRModel details: Phaser MODE: MR_AUTO
Highest resolutionLowest resolution
Rotation3.09 Å28.54 Å
Translation3.09 Å28.54 Å

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
SCALA3.3.21data scaling
PHASER2.5.5phasing
PDB_EXTRACT3.2data extraction
iMOSFLMdata reduction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TJ2

3tj2


Resolution: 1.85→30 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.957 / SU B: 8.688 / SU ML: 0.133 / SU R Cruickshank DPI: 0.1355 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.135 / ESU R Free: 0.13 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.234 2033 5 %RANDOM
Rwork0.198 ---
obs0.1998 38383 98.21 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 97.33 Å2 / Biso mean: 45.25 Å2 / Biso min: 26.53 Å2
Baniso -1Baniso -2Baniso -3
1--0.01 Å2-0 Å2-0 Å2
2--4.18 Å2-0 Å2
3----4.17 Å2
Refinement stepCycle: final / Resolution: 1.85→30 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms3013 0 188 85 3286
Biso mean--38.85 42.55 -
Num. residues----382
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0180.0193287
X-RAY DIFFRACTIONr_bond_other_d0.0030.023141
X-RAY DIFFRACTIONr_angle_refined_deg2.2992.0494462
X-RAY DIFFRACTIONr_angle_other_deg0.95237183
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.7755380
X-RAY DIFFRACTIONr_dihedral_angle_2_deg41.69323.361119
X-RAY DIFFRACTIONr_dihedral_angle_3_deg18.04415545
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8311515
X-RAY DIFFRACTIONr_chiral_restr0.1240.2495
X-RAY DIFFRACTIONr_gen_planes_refined0.010.0213591
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02752
X-RAY DIFFRACTIONr_mcbond_it2.5783.1721526
X-RAY DIFFRACTIONr_mcbond_other2.5773.1711525
X-RAY DIFFRACTIONr_mcangle_it3.5264.7331901
LS refinement shellResolution: 1.85→1.898 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.367 156 -
Rwork0.359 2734 -
all-2890 -
obs--98.1 %
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)
11.84060.22930.52951.6521-0.1066.4128-0.0829-0.1301-0.02070.00750.08780.16390.1014-0.1534-0.00490.14180.0190.02510.01920.01290.033741.361325.332110.6213
22.17810.1210.24522.08630.68556.3764-0.00780.0663-0.0509-0.08360.07460.1501-0.3929-0.1802-0.06690.06850.010.010.01630.01790.039542.754311.7598-11.2154
32.5211-0.16980.53971.63590.19544.50880.18350.0271-0.25360.0223-0.0487-0.050.22910.0882-0.13480.06750.0182-0.02670.020.00840.040746.8832.2706-32.8135
41.496-0.22430.41082.52360.00285.60510.046-0.0279-0.15060.1059-0.0222-0.05610.28710.4376-0.02390.0659-0.015-0.01730.13080.0120.019950.361341.1143-31.4345
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A17 - 110
2X-RAY DIFFRACTION2B17 - 114
3X-RAY DIFFRACTION3C17 - 111
4X-RAY DIFFRACTION4D17 - 111

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