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- PDB-7ad0: X-ray structure of Mdm2 with modified p53 peptide -

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Basic information

Entry
Database: PDB / ID: 7ad0
TitleX-ray structure of Mdm2 with modified p53 peptide
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Modified p53 peptide
KeywordsLIGASE / p53 / Mdm2 / MdmX / protein-protein interaction / inhibitor / cancer
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 / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / 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 / atrial septum development / regulation of protein catabolic process at postsynapse, modulating synaptic transmission / fibroblast activation / Trafficking of AMPA receptors / receptor serine/threonine kinase binding / peroxisome proliferator activated receptor binding / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / positive regulation of vascular associated smooth muscle cell migration / negative regulation of protein processing / SUMO transferase activity / response to steroid hormone / AKT phosphorylates targets in the cytosol / response to iron ion / NEDD8 ligase activity / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / endocardial cushion morphogenesis / ventricular septum development / positive regulation of muscle cell differentiation / cardiac septum morphogenesis / regulation of postsynaptic neurotransmitter receptor internalization / blood vessel development / SUMOylation of ubiquitinylation proteins / ligase activity / cellular response to alkaloid / Constitutive Signaling by AKT1 E17K in Cancer / regulation of protein catabolic process / negative regulation of signal transduction by p53 class mediator / negative regulation of DNA damage response, signal transduction by p53 class mediator / SUMOylation of transcription factors / response to magnesium ion / cellular response to UV-C / protein sumoylation / cellular response to actinomycin D / cellular response to estrogen stimulus / blood vessel remodeling / 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 / proteolysis involved in protein catabolic process / positive regulation of protein export from nucleus / ubiquitin binding / response to cocaine / DNA damage response, signal transduction by p53 class mediator / Stabilization of p53 / establishment of protein localization / Regulation of RUNX3 expression and activity / cellular response to gamma radiation / Oncogene Induced Senescence / RING-type E3 ubiquitin transferase / protein destabilization / Regulation of TP53 Activity through Methylation / cellular response to growth factor stimulus / response to toxic substance / centriolar satellite / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / disordered domain specific binding / p53 binding / ubiquitin protein ligase activity / endocytic vesicle membrane / 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 / Ub-specific processing proteases / postsynaptic density / protein ubiquitination / response to xenobiotic stimulus / protein domain specific binding / response to antibiotic / negative regulation of DNA-templated transcription / positive regulation of cell population proliferation / apoptotic process / 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 / 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. ...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 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
Similarity search - Domain/homology
E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.07 Å
AuthorsTwarda-Clapa, A. / Fortuna, P. / Grudnik, P. / Dubin, G. / Berlicki, L. / Holak, T.A.
CitationJournal: Eur.J.Med.Chem. / Year: 2020
Title: Systematic ""foldamerization"" of peptide inhibiting p53-MDM2/X interactions by the incorporation of trans- or cis-2-aminocyclopentanecarboxylic acid residues
Authors: Fortuna, P. / Twarda-Clapa, A. / Skalniak, L. / Ozga, K. / Holak, T.A. / Berlicki, L.
History
DepositionSep 13, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 28, 2020Provider: repository / Type: Initial release
Revision 1.1Oct 26, 2022Group: Database references / Category: citation / database_2
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.title / _database_2.pdbx_DOI / _database_2.pdbx_database_accession
Revision 2.0Nov 15, 2023Group: Atomic model / Data collection / Derived calculations
Category: atom_site / atom_site_anisotrop ...atom_site / atom_site_anisotrop / chem_comp_atom / chem_comp_bond / pdbx_validate_main_chain_plane / pdbx_validate_rmsd_angle / struct_conn
Item: _atom_site.auth_atom_id / _atom_site.label_atom_id ..._atom_site.auth_atom_id / _atom_site.label_atom_id / _atom_site_anisotrop.pdbx_auth_atom_id / _atom_site_anisotrop.pdbx_label_atom_id / _struct_conn.pdbx_leaving_atom_flag / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr2_label_atom_id
Revision 2.1Jan 31, 2024Group: Refinement description / Category: pdbx_initial_refinement_model

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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
C: E3 ubiquitin-protein ligase Mdm2
D: E3 ubiquitin-protein ligase Mdm2
E: E3 ubiquitin-protein ligase Mdm2
F: E3 ubiquitin-protein ligase Mdm2
H: Modified p53 peptide
I: Modified p53 peptide
J: Modified p53 peptide
K: Modified p53 peptide
L: Modified p53 peptide
M: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)73,16012
Polymers73,16012
Non-polymers00
Water2,972165
1
A: E3 ubiquitin-protein ligase Mdm2
H: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)12,1932
Polymers12,1932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1210 Å2
ΔGint-11 kcal/mol
Surface area6090 Å2
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
I: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)12,1932
Polymers12,1932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1190 Å2
ΔGint-12 kcal/mol
Surface area6170 Å2
MethodPISA
3
C: E3 ubiquitin-protein ligase Mdm2
J: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)12,1932
Polymers12,1932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-11 kcal/mol
Surface area5830 Å2
MethodPISA
4
D: E3 ubiquitin-protein ligase Mdm2
K: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)12,1932
Polymers12,1932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-12 kcal/mol
Surface area6090 Å2
MethodPISA
5
E: E3 ubiquitin-protein ligase Mdm2
L: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)12,1932
Polymers12,1932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1200 Å2
ΔGint-12 kcal/mol
Surface area5980 Å2
MethodPISA
6
F: E3 ubiquitin-protein ligase Mdm2
M: Modified p53 peptide


Theoretical massNumber of molelcules
Total (without water)12,1932
Polymers12,1932
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1170 Å2
ΔGint-11 kcal/mol
Surface area6010 Å2
MethodPISA
Unit cell
Length a, b, c (Å)46.811, 76.082, 197.299
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 10642.509 Da / Num. of mol.: 6
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli BL21(DE3) (bacteria)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide
Modified p53 peptide


Mass: 1550.751 Da / Num. of mol.: 6 / Source method: obtained synthetically
Details: This short chain is a modified p53 peptide. 475 is a modified aminoacid that was introduced to this chemically synthesized peptide to increase the affinity to Mdm2. N- and C-terminal ...Details: This short chain is a modified p53 peptide. 475 is a modified aminoacid that was introduced to this chemically synthesized peptide to increase the affinity to Mdm2. N- and C-terminal alanines in this peptide are the terminal modifications: acetyl group at the N-terminus, and amide group at the C-terminus.
Source: (synth.) Homo sapiens (human)
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 165 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY

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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: 2.36 Å3/Da / Density % sol: 47.94 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 5.5
Details: 0.1 M Bis-Tris pH 5.5 with 0.2 M NaCl and 25% PEG 3350

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: BESSY / Beamline: 14.1 / Wavelength: 0.97 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Dec 3, 2016
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.97 Å / Relative weight: 1
ReflectionResolution: 2.07→49.33 Å / Num. obs: 43882 / % possible obs: 99.5 % / Redundancy: 13.12 % / Rrim(I) all: 0.115 / Net I/σ(I): 16.98
Reflection shellResolution: 2.07→2.144 Å / Num. unique obs: 4309 / Rrim(I) all: 1.318

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Processing

Software
NameVersionClassification
REFMAC5.8.0049refinement
PDB_EXTRACT3.22data extraction
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 3TJ2

3tj2


Resolution: 2.07→49.32 Å / Cor.coef. Fo:Fc: 0.967 / Cor.coef. Fo:Fc free: 0.946 / SU B: 13.692 / SU ML: 0.169 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.194 / ESU R Free: 0.176 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : WITH TLS ADDED
RfactorNum. reflection% reflectionSelection details
Rfree0.2385 2100 4.8 %RANDOM
Rwork0.1871 ---
obs0.1895 41868 99.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 122.29 Å2 / Biso mean: 49.976 Å2 / Biso min: 17.22 Å2
Baniso -1Baniso -2Baniso -3
1-4.41 Å2-0 Å20 Å2
2--0.74 Å20 Å2
3----5.14 Å2
Refinement stepCycle: final / Resolution: 2.07→49.32 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4960 0 0 165 5125
Biso mean---46.1 -
Num. residues----608
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0150.025096
X-RAY DIFFRACTIONr_bond_other_d0.0010.025061
X-RAY DIFFRACTIONr_angle_refined_deg1.7992.0036891
X-RAY DIFFRACTIONr_angle_other_deg1.267311654
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.9615584
X-RAY DIFFRACTIONr_dihedral_angle_2_deg44.52223.46211
X-RAY DIFFRACTIONr_dihedral_angle_3_deg17.83815952
X-RAY DIFFRACTIONr_dihedral_angle_4_deg24.4071524
X-RAY DIFFRACTIONr_chiral_restr0.150.2786
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.025470
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021152
LS refinement shellResolution: 2.07→2.12 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.325 148 -
Rwork0.329 2965 -
obs--96.02 %
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)
11.9335-0.3615-0.89923.2872-0.10572.66130.2530.33180.3831-0.2903-0.0340.1641-0.5325-0.4576-0.21890.24990.14320.03320.26910.08810.2564-4.35221.9377-27.2373
21.3587-0.72460.49943.4957-0.99392.77580.0110.00140.13880.0169-0.0062-0.08790.0117-0.0499-0.00480.0011-0.01230.00210.18730.01660.185216.5044-15.6474-27.1496
32.3380.6551-1.27511.74220.86534.28990.0869-0.1228-0.01490.49820.2729-0.34130.5090.6111-0.35980.21990.1303-0.09110.199-0.04350.210317.188734.8629-39.1267
42.06250.53440.58561.6238-0.96922.8265-0.0264-0.0875-0.01180.03020.13620.03820.0416-0.1686-0.10970.05330.02390.0170.19310.02140.2266-6.8184-4.865-37.7168
51.33791.3814-0.07373.286-1.01862.5011-0.05480.1873-0.0342-0.3580.0422-0.11520.2257-0.05550.01260.17530.05710.020.16150.00890.1556-2.807-12.54335.1294
61.17680.15210.24443.5247-1.36823.82430.0731-0.19250.00460.4383-0.1451-0.2495-0.39150.04450.0720.1456-0.026-0.0190.15980.00640.16762.2712.2655-5.7415
73.7122.46531.50792.26911.81014.27060.22850.34170.08660.1085-0.1414-0.2548-0.32650.0268-0.08710.12160.00620.01820.34120.16310.29285.467915.9586-22.3939
81.7505-2.78470.12394.5468-0.75378.145-0.04240.14810.2270.1675-0.1557-0.4282-0.02630.33590.19810.1340.0572-0.05090.2732-0.00160.249525.876-21.6232-21.4586
93.74361.5994-1.35745.32740.96977.7705-0.06180.11130.40870.50860.2786-0.0432-0.3257-0.0035-0.21680.11750.04270.00730.12850.00730.18097.28539.638-44.4882
104.8861.78941.60233.31530.70265.5188-0.3435-0.32360.32420.19240.35670.3292-0.2467-0.3496-0.01320.07580.0730.02650.17290.05450.2214-15.26432.3521-43.2999
115.94014.846-1.03584.8607-1.70791.0676-0.0323-0.1592-0.3107-0.5277-0.1267-0.34040.44410.08030.1590.307-0.01260.06330.1586-0.00260.1843-1.7669-23.589410.6367
123.8976-2.6517-1.04415.4673-0.28026.53570.1277-0.03410.6730.5141-0.3135-0.523-0.69570.35790.18580.3732-0.04360.00240.2153-0.02550.32982.852723.2936-11.3235
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A24 - 113
2X-RAY DIFFRACTION2B25 - 111
3X-RAY DIFFRACTION3C25 - 110
4X-RAY DIFFRACTION4D25 - 111
5X-RAY DIFFRACTION5E25 - 111
6X-RAY DIFFRACTION6F25 - 111
7X-RAY DIFFRACTION7H16 - 29
8X-RAY DIFFRACTION8I16 - 29
9X-RAY DIFFRACTION9J16 - 29
10X-RAY DIFFRACTION10K16 - 29
11X-RAY DIFFRACTION11L16 - 29
12X-RAY DIFFRACTION12M16 - 29

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