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- PDB-6h22: Crystal structure of Mdm2 bound to a stapled peptide -

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Basic information

Entry
Database: PDB / ID: 6h22
TitleCrystal structure of Mdm2 bound to a stapled peptide
Components
  • E3 ubiquitin-protein ligase Mdm2
  • Stapled peptide
KeywordsLIGASE / Stapled peptide / Inhibitor / E3-ligase
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 / 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 / traversing start control point of mitotic cell cycle / negative regulation of intrinsic apoptotic signaling pathway by p53 class mediator / response to ether / 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 / atrioventricular valve morphogenesis / cellular response to peptide hormone stimulus / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / SUMOylation of ubiquitinylation proteins / cellular response to alkaloid / 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 / ligase activity / response to magnesium ion / protein sumoylation / SUMOylation of transcription factors / protein localization to nucleus / cellular response to UV-C / blood vessel remodeling / cellular response to estrogen stimulus / protein autoubiquitination / cellular response to actinomycin D / ribonucleoprotein complex binding / positive regulation of vascular associated smooth muscle cell proliferation / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / NPAS4 regulates expression of target genes / transcription repressor complex / regulation of heart rate / positive regulation of mitotic cell cycle / proteolysis involved in protein catabolic process / 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 / Signaling by ALK fusions and activated point mutants / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / cellular response to gamma radiation / response to toxic substance / cellular response to growth factor stimulus / cellular response to hydrogen peroxide / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / disordered domain specific binding / Regulation of TP53 Degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / p53 binding / negative regulation of neuron projection development / 5S rRNA binding / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / regulation of gene expression / proteasome-mediated ubiquitin-dependent protein catabolic process / protein-containing complex assembly / Oxidative Stress Induced Senescence / Regulation of TP53 Activity through Phosphorylation / amyloid fibril formation / regulation of cell cycle / protein ubiquitination / 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 / enzyme binding / negative regulation of transcription by RNA polymerase II / protein-containing complex / zinc ion binding / nucleoplasm
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
Chem-FL5 / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.006 Å
AuthorsWang, X. / Sharma, K. / Spring, D.R. / Hyvonen, M.
CitationJournal: Org.Biomol.Chem. / Year: 2019
Title: Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry.
Authors: Sharma, K. / Strizhak, A.V. / Fowler, E. / Wang, X. / Xu, W. / Hatt Jensen, C. / Wu, Y. / Sore, H.F. / Lau, Y.H. / Hyvonen, M. / Itzhaki, L.S. / Spring, D.R.
History
DepositionJul 12, 2018Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jul 31, 2019Provider: repository / Type: Initial release
Revision 1.1Aug 28, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.2Sep 11, 2019Group: Data collection / Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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: Stapled peptide
D: Stapled peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)25,8986
Polymers25,0114
Non-polymers8872
Water3,441191
1
A: E3 ubiquitin-protein ligase Mdm2
C: Stapled peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,9493
Polymers12,5062
Non-polymers4441
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1740 Å2
ΔGint-12 kcal/mol
Surface area5970 Å2
MethodPISA
2
B: E3 ubiquitin-protein ligase Mdm2
D: Stapled peptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)12,9493
Polymers12,5062
Non-polymers4441
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1690 Å2
ΔGint-11 kcal/mol
Surface area5960 Å2
MethodPISA
Unit cell
Length a, b, c (Å)64.416, 72.186, 45.124
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: 11081.952 Da / Num. of mol.: 2 / Mutation: E69AK70A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: MDM2 / Production host: Escherichia coli (E. coli)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase
#2: Protein/peptide Stapled peptide /


Mass: 1423.591 Da / Num. of mol.: 2 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
#3: Chemical ChemComp-FL5 / 12-(dimethylamino)-3,10-diethyl-N,N,N-trimethyl-3,10-dihydrodibenzo[3,4:7,8]cycloocta[1,2-d:5,6-d']bis([1,2,3]triazole)-5-aminium


Mass: 443.567 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C25H31N8 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 191 / 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: 2.17 Å3/Da / Density % sol: 43.42 %
Crystal growTemperature: 292.15 K / Method: vapor diffusion, sitting drop
Details: 1.1 M sodium malonate dibasic, 0.1 M HEPES pH 7.0, 0.5% v/v Jeffamine ED-2003

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 6, 2017
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2→72.19 Å / Num. obs: 14472 / % possible obs: 98.6 % / Redundancy: 5.4 % / Biso Wilson estimate: 29.04 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.111 / Rpim(I) all: 0.053 / Rrim(I) all: 0.123 / Net I/σ(I): 9.4
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. unique obsCC1/2Rpim(I) allRrim(I) all% possible all
2.01-2.115.40.73218980.9080.3440.81190.9
6.34-72.194.60.0375480.9990.0190.04299.9

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Processing

Software
NameVersionClassification
PHENIX1.9_1692refinement
Aimless0.5.32data scaling
PDB_EXTRACT3.24data extraction
XDSdata reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 2.006→48.062 Å / SU ML: 0.22 / Cross valid method: THROUGHOUT / σ(F): 0.31 / Phase error: 31.59
RfactorNum. reflection% reflection
Rfree0.2384 743 5.16 %
Rwork0.2107 --
obs0.2122 14409 98.42 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å
Displacement parametersBiso max: 64.34 Å2 / Biso mean: 30.0421 Å2 / Biso min: 15.78 Å2
Refinement stepCycle: final / Resolution: 2.006→48.062 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1700 0 66 191 1957
Biso mean--26.92 34.95 -
Num. residues----211
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0051823
X-RAY DIFFRACTIONf_angle_d0.8822475
X-RAY DIFFRACTIONf_chiral_restr0.032268
X-RAY DIFFRACTIONf_plane_restr0.005355
X-RAY DIFFRACTIONf_dihedral_angle_d14.577715
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Rfactor Rfree error: 0 / Total num. of bins used: 5

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkNum. reflection all% reflection obs (%)
2.0064-2.16130.37061330.30152535266893
2.1613-2.37880.29061480.262827362884100
2.3788-2.7230.26851550.239327152870100
2.723-3.43050.25021560.216927852941100
3.4305-48.07590.18651510.166728953046100

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