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- PDB-6i29: X-ray structure of the p53-MDM2 inhibitor NMI801 bound to HDM2 at... -

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Basic information

Entry
Database: PDB / ID: 6i29
TitleX-ray structure of the p53-MDM2 inhibitor NMI801 bound to HDM2 at 2.1A resolution
ComponentsHuman E3 Ubiquitin-Protein Ligase MDM2
KeywordsLIGASE / LEAD OPTIMIZATION
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 / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / cellular response to alkaloid / blood vessel development / regulation of protein catabolic process / cardiac septum morphogenesis / Constitutive Signaling by AKT1 E17K in Cancer / ligase activity / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / 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 / NPAS4 regulates expression of target genes / transcription repressor complex / 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 / Regulation of RUNX3 expression and activity / protein destabilization / 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 gamma radiation / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / p53 binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / cellular response to hypoxia / 5S rRNA binding / ubiquitin-dependent protein catabolic process / regulation of gene expression / protein-containing complex assembly / proteasome-mediated ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / Ub-specific processing proteases / regulation of cell cycle / protein ubiquitination / 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 / enzyme binding / negative regulation of transcription by RNA polymerase II / 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-H0W / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo Sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.1 Å
AuthorsKallen, J.
CitationJournal: To be published
Title: p53 dynamics vary between tissues and are linked with radiation sensitivity
Authors: Ornstein, J. / Iwamoto, Y. / Prytyskach, M. / Miller, M. / Kallen, J. / Ferretti, S. / Holzer, P. / Forrester, W. / Weissleder, R. / Lahav, G.
History
DepositionNov 1, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 20, 2019Provider: repository / Type: Initial release
Revision 1.1Jan 24, 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

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Assembly

Deposited unit
A: Human E3 Ubiquitin-Protein Ligase MDM2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8912
Polymers11,1561
Non-polymers7351
Water81145
1
A: Human E3 Ubiquitin-Protein Ligase MDM2
hetero molecules

A: Human E3 Ubiquitin-Protein Ligase MDM2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,7814
Polymers22,3122
Non-polymers1,4692
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation26_555-x,-y+1/2,z1
Buried area1640 Å2
ΔGint-9 kcal/mol
Surface area11140 Å2
MethodPISA
Unit cell
Length a, b, c (Å)121.883, 121.883, 121.883
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number214
Space group name H-MI4132
Components on special symmetry positions
IDModelComponents
11A-301-

HOH

21A-312-

HOH

31A-315-

HOH

41A-326-

HOH

51A-330-

HOH

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Components

#1: Protein Human E3 Ubiquitin-Protein Ligase MDM2


Mass: 11156.052 Da / Num. of mol.: 1 / Fragment: N-terminal domain, p53 binding domain
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo Sapiens (human) / Plasmid: pET28-derived vector / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 / References: UniProt: Q00987
#2: Chemical ChemComp-H0W / 6-chloranyl-3-[3-[(1~{S})-1-(4-chlorophenyl)ethyl]-5-phenyl-imidazol-4-yl]-~{N}-[2-[4-(2-oxidanylidene-1,3-oxazinan-3-yl)piperidin-1-yl]pyridin-3-yl]-1~{H}-indole-2-carboxamide


Mass: 734.673 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C40H37Cl2N7O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 45 / 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: 3.38 Å3/Da / Density % sol: 63.62 %
Crystal growTemperature: 298 K / Method: vapor diffusion, hanging drop / pH: 3.5 / Details: 2.1M (NH4)SO4, 0.1M Citrate pH 3.5

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X10SA / Wavelength: 1.0007 Å
DetectorType: PSI PILATUS 6M / Detector: PIXEL / Date: May 6, 2011
RadiationMonochromator: SI 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0007 Å / Relative weight: 1
ReflectionResolution: 2.1→19.27 Å / Num. obs: 9337 / % possible obs: 99.8 % / Redundancy: 36.5 % / Biso Wilson estimate: 46.8 Å2 / Rmerge(I) obs: 0.057 / Rpim(I) all: 0.022 / Rrim(I) all: 0.058 / Net I/σ(I): 45.1
Reflection shellResolution: 2.1→2.15 Å / Redundancy: 38.4 % / Rmerge(I) obs: 0.361 / Mean I/σ(I) obs: 11.3 / Rpim(I) all: 0.118 / Rrim(I) all: 0.366 / % possible all: 100

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
XSCALEdata scaling
PHASERphasing
REFMACrefinement
PDB_EXTRACT3.24data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4DIJ

4dij


Resolution: 2.1→19.27 Å / Cor.coef. Fo:Fc: 0.934 / Cor.coef. Fo:Fc free: 0.897 / SU B: 4.125 / SU ML: 0.114 / SU R Cruickshank DPI: 0.2067 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.207 / ESU R Free: 0.185
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2772 466 5 %RANDOM
Rwork0.2428 ---
obs0.2444 8869 100 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 73.18 Å2 / Biso mean: 43.373 Å2 / Biso min: 26.44 Å2
Refinement stepCycle: final / Resolution: 2.1→19.27 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms764 0 52 45 861
Biso mean--36.51 48.14 -
Num. residues----93
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.022838
X-RAY DIFFRACTIONr_angle_refined_deg1.0492.071136
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.207592
X-RAY DIFFRACTIONr_dihedral_angle_2_deg40.77123.93933
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.44315152
X-RAY DIFFRACTIONr_dihedral_angle_4_deg8.684154
X-RAY DIFFRACTIONr_chiral_restr0.0730.2123
X-RAY DIFFRACTIONr_gen_planes_refined0.0050.021615
LS refinement shellResolution: 2.1→2.154 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.27 34 -
Rwork0.258 645 -
all-679 -
obs--100 %

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