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- PDB-2z5t: Molecular basis for the inhibition of p53 by Mdmx -

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Basic information

Entry
Database: PDB / ID: 2z5t
TitleMolecular basis for the inhibition of p53 by Mdmx
Components
  • Cellular tumor antigen p53
  • Mdm4 protein
KeywordsCELL CYCLE / MDMX / MDM4 / MDM2 / p53 / Acetylation / Activator / Anti-oncogene / Apoptosis / Cytoplasm / Disease mutation / DNA-binding / Endoplasmic reticulum / Nucleus / Phosphorylation / Polymorphism / Transcription regulation
Function / homology
Function and homology information


Oxidative Stress Induced Senescence / Oncogene Induced Senescence / Regulation of TP53 Degradation / Stabilization of p53 / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 ...Oxidative Stress Induced Senescence / Oncogene Induced Senescence / Regulation of TP53 Degradation / Stabilization of p53 / Loss of function of TP53 in cancer due to loss of tetramerization ability / Regulation of TP53 Expression / signal transduction by p53 class mediator / negative regulation of G1 to G0 transition / negative regulation of glucose catabolic process to lactate via pyruvate / Transcriptional activation of cell cycle inhibitor p21 / regulation of intrinsic apoptotic signaling pathway by p53 class mediator / Activation of NOXA and translocation to mitochondria / negative regulation of pentose-phosphate shunt / ATP-dependent DNA/DNA annealing activity / negative regulation of helicase activity / regulation of cell cycle G2/M phase transition / intrinsic apoptotic signaling pathway in response to hypoxia / regulation of fibroblast apoptotic process / oxidative stress-induced premature senescence / oligodendrocyte apoptotic process / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / regulation of tissue remodeling / glucose catabolic process to lactate via pyruvate / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / mRNA transcription / circadian behavior / bone marrow development / histone deacetylase regulator activity / germ cell nucleus / regulation of mitochondrial membrane permeability involved in apoptotic process / RUNX3 regulates CDKN1A transcription / regulation of DNA damage response, signal transduction by p53 class mediator / TP53 regulates transcription of additional cell cycle genes whose exact role in the p53 pathway remain uncertain / TP53 Regulates Transcription of Death Receptors and Ligands / Activation of PUMA and translocation to mitochondria / DNA damage response, signal transduction by p53 class mediator resulting in transcription of p21 class mediator / negative regulation of glial cell proliferation / negative regulation of neuroblast proliferation / Regulation of TP53 Activity through Association with Co-factors / mitochondrial DNA repair / T cell lineage commitment / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / ER overload response / negative regulation of DNA replication / B cell lineage commitment / thymocyte apoptotic process / positive regulation of cardiac muscle cell apoptotic process / TP53 regulates transcription of several additional cell death genes whose specific roles in p53-dependent apoptosis remain uncertain / TP53 Regulates Transcription of Caspase Activators and Caspases / cardiac septum morphogenesis / entrainment of circadian clock by photoperiod / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / positive regulation of release of cytochrome c from mitochondria / necroptotic process / Zygotic genome activation (ZGA) / positive regulation of execution phase of apoptosis / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / rRNA transcription / negative regulation of telomere maintenance via telomerase / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / general transcription initiation factor binding / Transcriptional Regulation by VENTX / DNA damage response, signal transduction by p53 class mediator / replicative senescence / response to X-ray / intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress / mitophagy / cellular response to UV-C / positive regulation of RNA polymerase II transcription preinitiation complex assembly / hematopoietic stem cell differentiation / neuroblast proliferation / negative regulation of reactive oxygen species metabolic process / intrinsic apoptotic signaling pathway in response to DNA damage by p53 class mediator / chromosome organization / T cell proliferation involved in immune response / Pyroptosis / embryonic organ development / glial cell proliferation / viral process / cis-regulatory region sequence-specific DNA binding / TP53 Regulates Transcription of Genes Involved in G1 Cell Cycle Arrest / hematopoietic progenitor cell differentiation / type II interferon-mediated signaling pathway / somitogenesis / cellular response to actinomycin D / core promoter sequence-specific DNA binding / cellular response to glucose starvation / negative regulation of stem cell proliferation / positive regulation of intrinsic apoptotic signaling pathway / negative regulation of fibroblast proliferation / gastrulation / MDM2/MDM4 family protein binding / response to salt stress / cardiac muscle cell apoptotic process
Similarity search - Function
MDM4 / : / MDM2 / SWIB/MDM2 domain / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Cellular tumor antigen p53, transactivation domain 2 ...MDM4 / : / MDM2 / SWIB/MDM2 domain / p53 negative regulator Mdm2/Mdm4 / SWIB/MDM2 domain / SWIB/MDM2 domain / SWIB/MDM2 domain profile. / SWIB/MDM2 domain superfamily / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / p53 family signature. / p53, tetramerisation domain / P53 tetramerisation motif / p53, DNA-binding domain / P53 DNA-binding domain / p53 tumour suppressor family / p53-like tetramerisation domain superfamily / p53/RUNT-type transcription factor, DNA-binding domain superfamily / 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 / p53-like transcription factor, DNA-binding / Zinc finger, RING/FYVE/PHD-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Cellular tumor antigen p53 / Protein Mdm4 / Protein Mdm4
Similarity search - Component
Biological speciesDanio rerio (zebrafish)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.3 Å
AuthorsPopowicz, G.M. / Czarna, A. / Rothweiler, U. / Szwagierczak, A. / Holak, T.A.
CitationJournal: Cell Cycle / Year: 2007
Title: Molecular basis for the inhibition of p53 by Mdmx.
Authors: Popowicz, G.M. / Czarna, A. / Rothweiler, U. / Szwagierczak, A. / Krajewski, M. / Weber, L. / Holak, T.A.
History
DepositionJul 17, 2007Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Nov 6, 2007Provider: repository / Type: Initial release
Revision 1.1May 3, 2008Group: Version format compliance
Revision 1.2Jul 13, 2011Group: Version format compliance
Revision 1.3Nov 6, 2019Group: Data collection / Database references / Category: citation / struct_ref_seq_dif
Item: _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _struct_ref_seq_dif.details
Revision 1.4Nov 10, 2021Group: Database references / Category: database_2 / struct_ref_seq_dif
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_ref_seq_dif.details
Revision 1.5Nov 1, 2023Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
M: Mdm4 protein
P: Cellular tumor antigen p53
N: Mdm4 protein
Q: Cellular tumor antigen p53
O: Mdm4 protein
R: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)52,4096
Polymers52,4096
Non-polymers00
Water6,395355
1
M: Mdm4 protein
P: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)17,4702
Polymers17,4702
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area890 Å2
ΔGint-10.2 kcal/mol
Surface area6090 Å2
MethodPISA
2
N: Mdm4 protein
Q: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)17,4702
Polymers17,4702
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area950 Å2
ΔGint-9.8 kcal/mol
Surface area6230 Å2
MethodPISA
3
O: Mdm4 protein
R: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)17,4702
Polymers17,4702
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area900 Å2
ΔGint-10.6 kcal/mol
Surface area6250 Å2
MethodPISA
Unit cell
Length a, b, c (Å)81.080, 30.540, 101.100
Angle α, β, γ (deg.)90.00, 102.94, 90.00
Int Tables number4
Space group name H-MP1211

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Components

#1: Protein Mdm4 protein / Zebrafish MDMX with L46V and V95L mutations


Mass: 15661.614 Da / Num. of mol.: 3 / Fragment: SWIB domain / Mutation: L46V, V95L
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Danio rerio (zebrafish) / Gene: mdm4 / Plasmid: pET-46 / Production host: Escherichia coli (E. coli) / References: UniProt: Q4V944, UniProt: Q7ZUW7*PLUS
#2: Protein/peptide Cellular tumor antigen p53 / Tumor suppressor p53 / Phosphoprotein p53 / Antigen NY-CO-13


Mass: 1807.973 Da / Num. of mol.: 3 / Fragment: TRANSACTIVATION DOMAIN / Source method: obtained synthetically / Details: RP HPLC Purified / References: UniProt: P04637
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 355 / 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: 47.16 %
Crystal growTemperature: 280 K / Method: vapor diffusion, sitting drop / pH: 6.5
Details: 30% PEG 300, 0.1M MES, pH6.5, VAPOR DIFFUSION, SITTING DROP, temperature 280K

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Data collection

DiffractionMean temperature: 90 K
Diffraction sourceSource: SYNCHROTRON / Site: MPG/DESY, HAMBURG / Beamline: BW6 / Wavelength: 1.05 Å
DetectorType: MAR CCD 130 mm / Detector: CCD / Date: Apr 28, 2007 / Details: mirror
RadiationMonochromator: mirror / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.05 Å / Relative weight: 1
ReflectionResolution: 2.3→30 Å / Num. all: 25273 / Num. obs: 23555 / % possible obs: 93.2 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Rmerge(I) obs: 0.093
Reflection shellResolution: 2.3→2.4 Å / Rmerge(I) obs: 0.25 / Mean I/σ(I) obs: 5.25 / % possible all: 96.3

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Processing

Software
NameVersionClassification
REFMAC5.2.0019refinement
MAR345dtbdata collection
XDSdata reduction
XSCALEdata scaling
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1T4F

1t4f


Resolution: 2.3→20 Å / Cor.coef. Fo:Fc: 0.913 / Cor.coef. Fo:Fc free: 0.863 / SU B: 6.268 / SU ML: 0.159 / Cross valid method: THROUGHOUT / σ(F): 2 / σ(I): 2 / ESU R: 0.272 / ESU R Free: 0.23 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.26443 1117 5.1 %RANDOM
Rwork0.21052 ---
all0.22 ---
obs0.21329 20789 98.95 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.4 Å / Solvent model: MASK
Displacement parametersBiso mean: 21.136 Å2
Baniso -1Baniso -2Baniso -3
1--0.69 Å20 Å2-0.64 Å2
2---1.02 Å20 Å2
3---1.43 Å2
Refinement stepCycle: LAST / Resolution: 2.3→20 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2487 0 0 355 2842
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0222544
X-RAY DIFFRACTIONr_angle_refined_deg1.1891.9853437
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.0625301
X-RAY DIFFRACTIONr_dihedral_angle_2_deg36.45424.455110
X-RAY DIFFRACTIONr_dihedral_angle_3_deg16.73715473
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.9761511
X-RAY DIFFRACTIONr_chiral_restr0.0860.2387
X-RAY DIFFRACTIONr_gen_planes_refined0.0030.021858
X-RAY DIFFRACTIONr_nbd_refined0.1930.21321
X-RAY DIFFRACTIONr_nbtor_refined0.2970.21705
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1510.2266
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.1760.250
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.1880.218
X-RAY DIFFRACTIONr_mcbond_it0.5731.51576
X-RAY DIFFRACTIONr_mcangle_it0.97622489
X-RAY DIFFRACTIONr_scbond_it1.30631081
X-RAY DIFFRACTIONr_scangle_it2.0454.5948
LS refinement shellResolution: 2.3→2.359 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.303 87 -
Rwork0.215 1491 -
obs--96.63 %

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