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- PDB-4hfz: Crystal Structure of an MDM2/P53 Peptide Complex -

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Basic information

Entry
Database: PDB / ID: 4hfz
TitleCrystal Structure of an MDM2/P53 Peptide Complex
Components
  • Cellular tumor antigen p53P53
  • E3 ubiquitin-protein ligase Mdm2
KeywordsLIGASE / MDM2 / p53 / Surface Entropy Reduction / Mutant Validation
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 / 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 / response to iron ion / negative regulation of miRNA processing / positive regulation of thymocyte apoptotic process / glucose catabolic process to lactate via pyruvate / regulation of tissue remodeling / peroxisome proliferator activated receptor binding / negative regulation of protein processing / positive regulation of mitochondrial membrane permeability / negative regulation of mitophagy / positive regulation of programmed necrotic cell death / response to steroid hormone / NEDD8 ligase activity / SUMO transferase activity / mRNA transcription / bone marrow development / circadian behavior / T cell proliferation involved in immune response / regulation of mitochondrial membrane permeability involved in apoptotic process / histone deacetylase regulator activity / RUNX3 regulates CDKN1A transcription / germ cell nucleus / AKT phosphorylates targets in the cytosol / regulation of DNA damage response, signal transduction by p53 class mediator / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / 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 neuroblast proliferation / ventricular septum development / endocardial cushion morphogenesis / negative regulation of glial cell proliferation / Formation of Senescence-Associated Heterochromatin Foci (SAHF) / Regulation of TP53 Activity through Association with Co-factors / positive regulation of execution phase of apoptosis / mitochondrial DNA repair / T cell lineage commitment / positive regulation of muscle cell differentiation / negative regulation of DNA replication / ER overload response / SUMOylation of ubiquitinylation proteins / B cell lineage commitment / cellular response to alkaloid / thymocyte apoptotic process / blood vessel development / 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 / regulation of protein catabolic process / TP53 Regulates Transcription of Caspase Activators and Caspases / entrainment of circadian clock by photoperiod / cardiac septum morphogenesis / PI5P Regulates TP53 Acetylation / Association of TriC/CCT with target proteins during biosynthesis / Constitutive Signaling by AKT1 E17K in Cancer / Zygotic genome activation (ZGA) / necroptotic process / negative regulation of DNA damage response, signal transduction by p53 class mediator / rRNA transcription / positive regulation of release of cytochrome c from mitochondria / response to magnesium ion / TP53 Regulates Transcription of Genes Involved in Cytochrome C Release / TFIID-class transcription factor complex binding / mitophagy / ligase activity / negative regulation of telomere maintenance via telomerase / protein sumoylation / SUMOylation of transcription factors / intrinsic apoptotic signaling pathway by p53 class mediator / protein localization to nucleus / neuroblast proliferation / general transcription initiation factor 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 / Cellular tumor antigen p53, transactivation domain 2 ...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 / Cellular tumor antigen p53, transactivation domain 2 / Transactivation domain 2 / p53 transactivation domain / P53 transactivation motif / Zn-finger in Ran binding protein and others / 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-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type / Orthogonal Bundle / Mainly Alpha
Similarity search - Domain/homology
Cellular tumor antigen p53 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.694 Å
AuthorsAnil, B. / Riedinger, C. / Endicott, J.A. / Noble, M.E.M.
CitationJournal: Acta Crystallogr.,Sect.D / Year: 2013
Title: The structure of an MDM2-Nutlin-3a complex solved by the use of a validated MDM2 surface-entropy reduction mutant.
Authors: Anil, B. / Riedinger, C. / Endicott, J.A. / Noble, M.E.
History
DepositionOct 5, 2012Deposition site: RCSB / Processing site: RCSB
Revision 1.0Jul 31, 2013Provider: repository / Type: Initial release
Revision 1.1Aug 21, 2013Group: Database references
Revision 1.2Feb 28, 2024Group: 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 / struct_ncs_dom_lim / 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_ncs_dom_lim.beg_auth_comp_id / _struct_ncs_dom_lim.beg_label_asym_id / _struct_ncs_dom_lim.beg_label_comp_id / _struct_ncs_dom_lim.beg_label_seq_id / _struct_ncs_dom_lim.end_auth_comp_id / _struct_ncs_dom_lim.end_label_asym_id / _struct_ncs_dom_lim.end_label_comp_id / _struct_ncs_dom_lim.end_label_seq_id / _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
B: Cellular tumor antigen p53
C: E3 ubiquitin-protein ligase Mdm2
D: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,5505
Polymers28,4544
Non-polymers961
Water86548
1
A: E3 ubiquitin-protein ligase Mdm2
B: Cellular tumor antigen p53
hetero molecules


Theoretical massNumber of molelcules
Total (without water)14,3233
Polymers14,2272
Non-polymers961
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-23 kcal/mol
Surface area5620 Å2
MethodPISA
2
C: E3 ubiquitin-protein ligase Mdm2
D: Cellular tumor antigen p53


Theoretical massNumber of molelcules
Total (without water)14,2272
Polymers14,2272
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1100 Å2
ΔGint-10 kcal/mol
Surface area6540 Å2
MethodPISA
Unit cell
Length a, b, c (Å)52.944, 52.944, 196.201
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number96
Space group name H-MP43212
Noncrystallographic symmetry (NCS)NCS domain:
IDEns-IDDetails
11A
21C

NCS domain segments:

Component-ID: 0 / Ens-ID: 1 / Beg auth comp-ID: THR / Beg label comp-ID: THR / End auth comp-ID: LEU / End label comp-ID: LEU / Refine code: 0 / Auth seq-ID: 26 - 107 / Label seq-ID: 10 - 91

Dom-IDAuth asym-IDLabel asym-ID
1AA
2CC

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Components

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


Mass: 12419.212 Da / Num. of mol.: 2 / Fragment: p53 binding domain (residues 17-125) / Mutation: E69A, K70A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Plasmid: pGEX6P1 / Production host: Escherichia coli (E. coli) / Strain (production host): BL21 (DE23)
References: UniProt: Q00987, Ligases; Forming carbon-nitrogen bonds; Acid-amino-acid ligases (peptide synthases)
#2: Protein/peptide Cellular tumor antigen p53 / P53 / Antigen NY-CO-13 / Phosphoprotein p53 / Tumor suppressor p53


Mass: 1807.973 Da / Num. of mol.: 2 / Fragment: residues 15-29 / Source method: obtained synthetically / Details: Synthetic construct / Source: (synth.) Homo sapiens (human) / References: UniProt: P04637
#3: Chemical ChemComp-SO4 / SULFATE ION / Sulfate


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


Mass: 18.015 Da / Num. of mol.: 48 / 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: 2.42 Å3/Da / Density % sol: 49.09 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.4
Details: 0.2 M (NH4)2SO4, pH 4.6 and 30% w/v PEG 8000, VAPOR DIFFUSION, SITTING DROP, temperature 277K

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Data collection

DiffractionMean temperature: 296 K
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 0.96 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Feb 28, 2011
RadiationMonochromator: Si 111 channel / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.96 Å / Relative weight: 1
ReflectionResolution: 2.694→46.68 Å / Num. obs: 8223 / % possible obs: 96.6 % / Observed criterion σ(F): 3 / Observed criterion σ(I): 5
Reflection shellResolution: 2.694→2.85 Å / % possible all: 99.8

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Processing

Software
NameVersionClassification
XDSdata scaling
PHASERphasing
REFMAC5.6.0117refinement
XDSdata reduction
SCALAdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.694→41.12 Å / Cor.coef. Fo:Fc: 0.93 / Cor.coef. Fo:Fc free: 0.896 / SU B: 19.73 / SU ML: 0.212 / Cross valid method: THROUGHOUT / σ(F): 10 / ESU R: 0.792 / ESU R Free: 0.323 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT
RfactorNum. reflection% reflectionSelection details
Rfree0.24679 376 4.6 %RANDOM
Rwork0.19527 ---
obs0.19777 7733 96.86 %-
all-8367 --
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 38.15 Å2
Baniso -1Baniso -2Baniso -3
1-1.43 Å20 Å20 Å2
2--1.43 Å20 Å2
3----2.85 Å2
Refinement stepCycle: LAST / Resolution: 2.694→41.12 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1620 0 5 48 1673
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0140.021669
X-RAY DIFFRACTIONr_angle_refined_deg1.6341.9972254
X-RAY DIFFRACTIONr_dihedral_angle_1_deg4.3045194
X-RAY DIFFRACTIONr_dihedral_angle_2_deg43.8723.62369
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.85915316
X-RAY DIFFRACTIONr_dihedral_angle_4_deg22.314158
X-RAY DIFFRACTIONr_chiral_restr0.1130.2258
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.0211200
Refine LS restraints NCS

Ens-ID: 1 / Number: 93 / Refine-ID: X-RAY DIFFRACTION / Type: interatomic distance / Rms dev position: 0.09 Å / Weight position: 0.05

Dom-IDAuth asym-ID
1A
2C
LS refinement shellResolution: 2.694→2.764 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.385 22 -
Rwork0.238 456 -
obs--93.73 %
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
13.7099-0.1048-0.70342.97260.58723.12360.04270.2070.0402-0.0134-0.0052-0.09020.08240.0846-0.03750.0508-0.0034-0.01610.12580.01920.01084.7063-23.284212.7627
221.3439-3.81672.639910.08310.499719.4178-0.50021.13280.835-0.160.4687-0.1461-0.473-0.07870.03160.2554-0.02070.02610.16650.07380.061-1.7881-15.60895.2208
32.9398-1.61570.68534.7997-1.46533.4995-0.0205-0.148-0.06380.09940.00970.07220.3598-0.13130.01080.09350.001-0.00510.1463-0.03510.0131-1.9057-25.620337.3351
43.8263-1.3903-2.532817.09730.988416.4292-0.28260.5665-0.2559-0.70810.31340.37790.8391-0.4089-0.03080.2391-0.0092-0.08790.2672-0.0090.1236-2.2163-35.004228.7519
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A26 - 108
2X-RAY DIFFRACTION2B17 - 27
3X-RAY DIFFRACTION3C25 - 108
4X-RAY DIFFRACTION4D17 - 27

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