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- PDB-5c5a: Crystal Structure of HDM2 in complex with Nutlin-3a -

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Basic information

Entry
Database: PDB / ID: 5c5a
TitleCrystal Structure of HDM2 in complex with Nutlin-3a
ComponentsE3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / Drug Design / HDM2 / complex structure
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 / SUMO transferase activity / response to steroid hormone / 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 / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / 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 / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / Stabilization of p53 / Regulation of RUNX3 expression and activity / protein destabilization / RING-type E3 ubiquitin transferase / cellular response to gamma radiation / 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 / negative regulation of neuron projection development / p53 binding / 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
IODIDE ION / Chem-NUT / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.146 Å
AuthorsOrts, J. / Waelti, M.A. / Marsh, M. / Vera, L. / Gossert, A.D. / Guentert, P. / Riek, R.
Funding support Switzerland, 3items
OrganizationGrant numberCountry
FEBS Switzerland
Lichtenberg program of the Volkswagen Foundation Switzerland
Japan Society for the Promotion of Science
CitationJournal: To Be Published
Title: NMR Molecular Replacement, NMR2
Authors: Orts, J. / Waelti, M.A. / Marsh, M. / Vera, L. / Gossert, A.D. / Guentert, P. / Riek, R.
History
DepositionJun 19, 2015Deposition site: RCSB / Processing site: PDBE
Revision 1.0Jun 29, 2016Provider: repository / Type: Initial release
Revision 1.1Jan 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)23,47512
Polymers21,5412
Non-polymers1,93410
Water3,099172
1
A: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,6115
Polymers10,7711
Non-polymers8404
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)11,8647
Polymers10,7711
Non-polymers1,0946
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)41.620, 43.630, 52.670
Angle α, β, γ (deg.)90.00, 90.04, 90.00
Int Tables number4
Space group name H-MP1211

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 10770.636 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pET15b / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)

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Non-polymers , 5 types, 182 molecules

#2: Chemical ChemComp-NUT / 4-({(4S,5R)-4,5-bis(4-chlorophenyl)-2-[4-methoxy-2-(propan-2-yloxy)phenyl]-4,5-dihydro-1H-imidazol-1-yl}carbonyl)piperazin-2-one / Nutlin 3a


Mass: 581.490 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C30H30Cl2N4O4
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Cl
#5: Chemical
ChemComp-IOD / IODIDE ION / Iodide


Mass: 126.904 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: I
#6: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 172 / Source method: isolated from a natural source / Formula: H2O

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Experimental details

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Experiment

ExperimentMethod: X-RAY DIFFRACTION

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Sample preparation

CrystalDensity Matthews: 2.19 Å3/Da / Density % sol: 43.9 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop / Details: 0.2M Potassium iodide, 2.2M Ammonium Sulfate

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: SLS / Beamline: X06DA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 2M-F / Detector: PIXEL / Date: Jun 12, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.146→41.62 Å / Num. obs: 53751 / % possible obs: 79.13 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.06794 / Net I/σ(I): 12.58
Reflection shellResolution: 1.146→1.187 Å / Redundancy: 1.2 % / % possible all: 12.95

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
XDSdata reduction
XDSdata scaling
PHENIXmodel building
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 4HG7

4hg7


Resolution: 1.146→41.62 Å / SU ML: 0.13 / Cross valid method: FREE R-VALUE / σ(F): 1.05 / Phase error: 21.11 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1683 3521 3.78 %
Rwork0.1531 --
obs0.1537 53749 69.83 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.146→41.62 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1512 0 96 172 1780
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0141708
X-RAY DIFFRACTIONf_angle_d1.5932322
X-RAY DIFFRACTIONf_dihedral_angle_d12.08702
X-RAY DIFFRACTIONf_chiral_restr0.189256
X-RAY DIFFRACTIONf_plane_restr0.009338
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.1456-1.16130.506140.4376162X-RAY DIFFRACTION3
1.1613-1.17790.4235240.355379X-RAY DIFFRACTION7
1.1779-1.19540.4497170.3235747X-RAY DIFFRACTION14
1.1954-1.21410.2936470.31521135X-RAY DIFFRACTION22
1.2141-1.2340.3461570.31731512X-RAY DIFFRACTION30
1.234-1.25530.2823820.33151965X-RAY DIFFRACTION38
1.2553-1.27810.2757900.30312417X-RAY DIFFRACTION48
1.2781-1.30270.32071160.28512958X-RAY DIFFRACTION57
1.3027-1.32930.27051430.28373431X-RAY DIFFRACTION67
1.3293-1.35820.32541680.26264046X-RAY DIFFRACTION78
1.3582-1.38980.34391520.25824227X-RAY DIFFRACTION83
1.3898-1.42460.30621780.23574421X-RAY DIFFRACTION85
1.4246-1.46310.21332060.20764345X-RAY DIFFRACTION86
1.4631-1.50610.18991790.19114588X-RAY DIFFRACTION89
1.5061-1.55480.23061780.17314698X-RAY DIFFRACTION92
1.5548-1.61030.1751950.15584676X-RAY DIFFRACTION92
1.6103-1.67480.18761650.14174874X-RAY DIFFRACTION93
1.6748-1.7510.15582160.12734759X-RAY DIFFRACTION95
1.751-1.84340.13881640.12894850X-RAY DIFFRACTION95
1.8434-1.95880.12811960.12224969X-RAY DIFFRACTION95
1.9588-2.11010.16281910.11154854X-RAY DIFFRACTION95
2.1101-2.32240.09671930.11214816X-RAY DIFFRACTION94
2.3224-2.65840.13871900.12824877X-RAY DIFFRACTION95
2.6584-3.34910.14921900.13164934X-RAY DIFFRACTION95
3.3491-41.64750.15221800.15094873X-RAY DIFFRACTION95

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