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- PDB-1t4f: Structure of human MDM2 in complex with an optimized p53 peptide -

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Basic information

Entry
Database: PDB / ID: 1t4f
TitleStructure of human MDM2 in complex with an optimized p53 peptide
Components
  • Ubiquitin-protein ligase E3 Mdm2
  • optimized p53 peptide
KeywordsLIGASE / MDM2-p53 peptide complex / p53-binding protein Mdm2 Oncoprotein Mdm2 Double minute 2 protein Hdm2
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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator ...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 / fibroblast activation / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / negative regulation of signal transduction by p53 class mediator / receptor serine/threonine kinase binding / Trafficking of AMPA receptors / peroxisome proliferator activated receptor binding / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to iron ion / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / response to steroid hormone / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / cellular response to alkaloid / SUMOylation of ubiquitinylation proteins / regulation of postsynaptic neurotransmitter receptor internalization / cardiac septum morphogenesis / blood vessel development / ligase activity / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / response to magnesium ion / SUMOylation of transcription factors / protein sumoylation / cellular response to UV-C / cellular response to estrogen stimulus / blood vessel remodeling / cellular response to actinomycin D / protein localization to nucleus / ribonucleoprotein complex binding / protein autoubiquitination / positive regulation of vascular associated smooth muscle cell proliferation / NPAS4 regulates expression of target genes / transcription repressor complex / positive regulation of mitotic cell cycle / regulation of heart rate / DNA damage response, signal transduction by p53 class mediator / proteolysis involved in protein catabolic process / ubiquitin binding / positive regulation of protein export from nucleus / Stabilization of p53 / response to cocaine / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / protein destabilization / cellular response to growth factor stimulus / RING-type E3 ubiquitin transferase / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / centriolar satellite / cellular response to hydrogen peroxide / response to toxic substance / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / p53 binding / endocytic vesicle membrane / ubiquitin protein ligase activity / Signaling by ALK fusions and activated point mutants / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / negative regulation of neuron projection development / 5S rRNA binding / protein-containing complex assembly / ubiquitin-dependent protein catabolic process / Oxidative Stress Induced Senescence / cellular response to hypoxia / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of cell cycle / postsynaptic density / Ub-specific processing proteases / protein ubiquitination / protein domain specific binding / response to xenobiotic stimulus / response to antibiotic / negative regulation of DNA-templated transcription / apoptotic process / positive regulation of cell population proliferation / ubiquitin protein ligase binding / positive regulation of gene expression / negative regulation of apoptotic process / nucleolus / glutamatergic synapse / enzyme binding
Similarity search - Function
E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 ...E3 ubiquitin-protein ligase Mdm2 / MDM2, modified RING finger, HC subclass / MDM2 / SWIB/MDM2 domain / 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 superfamily / Zinc finger RanBP2-type signature. / 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
E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.9 Å
AuthorsGrasberger, B.L. / Schubert, C. / Koblish, H.K. / Carver, T.E. / Franks, C.F. / Zhao, S.Y. / Lu, T. / LaFrance, L.V. / Parks, D.J.
CitationJournal: J.Med.Chem. / Year: 2005
Title: Discovery and cocrystal structure of benzodiazepinedione HDM2 antagonists that activate p53 in cells
Authors: Grasberger, B.L. / Lu, T. / Schubert, C. / Parks, D.J. / Carver, T.E. / Koblish, H.K. / Cummings, M.D. / LaFrance, L.V. / Milkiewicz, K.L.
History
DepositionApr 29, 2004Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 8, 2005Provider: repository / Type: Initial release
Revision 1.1Apr 30, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Aug 23, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / 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
Remark 999SEQUENCE THE AUTHOR INDICATED THAT CHAIN P WAS DERIVED FROM A PHAGE DISPLAY EXPERIMENT,THEREFORE ...SEQUENCE THE AUTHOR INDICATED THAT CHAIN P WAS DERIVED FROM A PHAGE DISPLAY EXPERIMENT,THEREFORE THERE ARE NO MATCHES IN THE SEQUENCE DATABASE

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
M: Ubiquitin-protein ligase E3 Mdm2
P: optimized p53 peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)13,9063
Polymers13,8102
Non-polymers961
Water1,06359
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-20 kcal/mol
Surface area5990 Å2
MethodPISA
Unit cell
Length a, b, c (Å)41.030, 43.590, 54.570
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 12592.401 Da / Num. of mol.: 1 / Mutation: 17-125, additional Gly at N-terminus
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Species (production host): Escherichia coli / Production host: Escherichia coli BL21 (bacteria) / Strain (production host): BL21
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide optimized p53 peptide


Mass: 1217.373 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 59 / 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: 2.12 Å3/Da / Density % sol: 41.5 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / pH: 9
Details: (NH4)2SO4, Bicine, pH 9.0, VAPOR DIFFUSION, HANGING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X12B / Wavelength: 0.9795 Å
DetectorType: ADSC QUANTUM 4 / Detector: CCD / Date: Nov 1, 2000
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 1.9→25 Å / Num. all: 7247 / Num. obs: 7247 / % possible obs: 88.9 % / Observed criterion σ(F): 0 / Observed criterion σ(I): -3 / Redundancy: 4 % / Biso Wilson estimate: 11 Å2 / Rmerge(I) obs: 0.025 / Net I/σ(I): 36.1
Reflection shellResolution: 1.9→1.97 Å / Redundancy: 2.8 % / Rmerge(I) obs: 0.072 / Mean I/σ(I) obs: 9.1 / Num. unique all: 456 / % possible all: 56.2

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Processing

Software
NameVersionClassification
CNX2000.1refinement
DENZOdata reduction
SCALEPACKdata scaling
CNX2000.1phasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1YCR

1ycr


Resolution: 1.9→23.13 Å / Rfactor Rfree error: 0.008 / Data cutoff high absF: 849537.54 / Data cutoff low absF: 0 / Isotropic thermal model: RESTRAINED / Cross valid method: THROUGHOUT / σ(F): 0 / Stereochemistry target values: Engh & Huber
RfactorNum. reflection% reflectionSelection details
Rfree0.231 786 10.8 %RANDOM
Rwork0.197 ---
all-7246 --
obs-7246 89.1 %-
Solvent computationSolvent model: FLAT MODEL / Bsol: 47.501 Å2 / ksol: 0.425854 e/Å3
Displacement parametersBiso mean: 18.2 Å2
Baniso -1Baniso -2Baniso -3
1-2.61 Å20 Å20 Å2
2---3.31 Å20 Å2
3---0.7 Å2
Refine analyze
FreeObs
Luzzati coordinate error0.25 Å0.2 Å
Luzzati d res low-5 Å
Luzzati sigma a0.14 Å0.07 Å
Refinement stepCycle: LAST / Resolution: 1.9→23.13 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms816 0 5 59 880
Refine LS restraints
Refine-IDTypeDev idealDev ideal target
X-RAY DIFFRACTIONc_bond_d0.006
X-RAY DIFFRACTIONc_angle_deg1.1
X-RAY DIFFRACTIONc_dihedral_angle_d20.6
X-RAY DIFFRACTIONc_improper_angle_d0.64
X-RAY DIFFRACTIONc_mcbond_it1.281.5
X-RAY DIFFRACTIONc_mcangle_it1.812
X-RAY DIFFRACTIONc_scbond_it2.342
X-RAY DIFFRACTIONc_scangle_it3.572.5
LS refinement shellResolution: 1.9→2.02 Å / Rfactor Rfree error: 0.024 / Total num. of bins used: 6
RfactorNum. reflection% reflection
Rfree0.229 93 11.3 %
Rwork0.187 729 -
obs--61.6 %
Xplor file
Refine-IDSerial noParam fileTopol file
X-RAY DIFFRACTION1PROTEIN_REP.PARAMPROTEIN.TOP
X-RAY DIFFRACTION2WATER_REP.PARAMION.TOP
X-RAY DIFFRACTION3ION.PARAMWATER.TOP

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