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- PDB-4mdn: Structure of a novel submicromolar MDM2 inhibitor -

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Basic information

Entry
Database: PDB / ID: 4mdn
TitleStructure of a novel submicromolar MDM2 inhibitor
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE/LIGASE INHIBITOR / MDM2 / p53 / cancer / small molecule / 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 / 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-Y30 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.905 Å
AuthorsBista, M. / Popowicz, G. / Holak, T.A.
CitationJournal: Structure / Year: 2013
Title: Transient Protein States in Designing Inhibitors of the MDM2-p53 Interaction.
Authors: Bista, M. / Wolf, S. / Khoury, K. / Kowalska, K. / Huang, Y. / Wrona, E. / Arciniega, M. / Popowicz, G.M. / Holak, T.A. / Domling, A.
History
DepositionAug 23, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Nov 13, 2013Provider: repository / Type: Initial release
Revision 1.1Dec 4, 2013Group: Database references
Revision 1.2Dec 25, 2013Group: Database references
Revision 1.3Feb 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

Downloads & links

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Assembly

Deposited unit
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8044
Polymers11,0291
Non-polymers7753
Water1,27971
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)64.341, 64.341, 81.685
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number92
Space group name H-MP41212

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Components

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


Mass: 11029.016 Da / Num. of mol.: 1 / Fragment: UNP residues 18-110
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-Y30 / 3-{(1S)-2-(tert-butylamino)-1-[{4-[(4-chlorobenzyl)oxy]benzyl}(formyl)amino]-2-oxoethyl}-6-chloro-1H-indole-2-carboxylic acid


Mass: 582.474 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H29Cl2N3O5
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 71 / 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: 3.83 Å3/Da / Density % sol: 67.91 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 8
Details: 0.2 M ammonium nitrate, 20% w/v PEG3350, pH 8.0, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA
DetectorType: PSI PILATUS 6M / Detector: PIXEL
RadiationMonochromator: double crystal Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthRelative weight: 1
ReflectionResolution: 1.905→50.544 Å / Num. all: 13977 / Num. obs: 13263 / % possible obs: 95 % / Biso Wilson estimate: 38.87 Å2
Reflection shellHighest resolution: 1.905 Å

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Processing

Software
NameVersionClassificationNB
PHENIX1.8.2_1309refinement
PDB_EXTRACT3.11data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.905→50.544 Å / Occupancy max: 1 / Occupancy min: 0.24 / FOM work R set: 0.8324 / SU ML: 0.21 / σ(F): 1.34 / Phase error: 22.65 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.203 658 4.97 %
Rwork0.1802 --
obs0.1813 13246 94.7 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso max: 123.6 Å2 / Biso mean: 42.7075 Å2 / Biso min: 24.06 Å2
Refinement stepCycle: LAST / Resolution: 1.905→50.544 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms773 0 50 71 894
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.008862
X-RAY DIFFRACTIONf_angle_d1.8761177
X-RAY DIFFRACTIONf_chiral_restr0.102128
X-RAY DIFFRACTIONf_plane_restr0.008142
X-RAY DIFFRACTIONf_dihedral_angle_d13.411328
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
1.905-2.05160.33011270.25972441256894
2.0516-2.25810.22881290.21332527265697
2.2581-2.58480.27141520.20362490264295
2.5848-3.25650.22531180.19292546266495
3.2565-50.56220.15971320.15732584271692
Refinement TLS params.Method: refined / Origin x: -16.3209 Å / Origin y: 0.0392 Å / Origin z: -2.4237 Å
111213212223313233
T0.2593 Å2-0.0007 Å20.0031 Å2-0.1541 Å20.0182 Å2--0.1937 Å2
L5.3084 °2-1.0656 °2-0.1636 °2-3.9691 °21.2356 °2--4.0116 °2
S0.0227 Å °0.1543 Å °0.1075 Å °-0.0242 Å °-0.0112 Å °-0.0117 Å °-0.0983 Å °-0.1305 Å °-0.0355 Å °
Refinement TLS groupSelection details: all

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