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- PDB-8p0d: Human 14-3-3 sigma in complex with human MDM2 peptide -

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Basic information

Entry
Database: PDB / ID: 8p0d
TitleHuman 14-3-3 sigma in complex with human MDM2 peptide
Components
  • 14-3-3 protein sigma
  • E3 ubiquitin-protein ligase Mdm2
KeywordsPROTEIN BINDING / SIGNALING PROTEIN-PEPTIDE complex
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 / response to iron ion / peroxisome proliferator activated receptor binding / negative regulation of protein processing / response to steroid hormone / SUMO transferase activity / NEDD8 ligase activity / AKT phosphorylates targets in the cytosol / cellular response to peptide hormone stimulus / atrioventricular valve morphogenesis / ventricular septum development / endocardial cushion morphogenesis / positive regulation of muscle cell differentiation / regulation of epidermal cell division / protein kinase C inhibitor activity / SUMOylation of ubiquitinylation proteins / cellular response to alkaloid / positive regulation of epidermal cell differentiation / keratinocyte development / blood vessel development / keratinization / 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 / response to magnesium ion / ligase activity / protein sumoylation / SUMOylation of transcription factors / Regulation of localization of FOXO transcription factors / protein localization to nucleus / keratinocyte proliferation / cellular response to actinomycin D / phosphoserine residue binding / cellular response to UV-C / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / blood vessel remodeling / establishment of skin barrier / cellular response to estrogen stimulus / protein autoubiquitination / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / ribonucleoprotein complex binding / DNA damage response, signal transduction by p53 class mediator resulting in cell cycle arrest / protein kinase A signaling / negative regulation of stem cell proliferation / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of vascular associated smooth muscle cell proliferation / transcription repressor complex / NPAS4 regulates expression of target genes / protein export from nucleus / negative regulation of innate immune response / regulation of heart rate / proteolysis involved in protein catabolic process / positive regulation of mitotic cell cycle / protein sequestering activity / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of protein export from nucleus / response to cocaine / ubiquitin binding / stem cell proliferation / Translocation of SLC2A4 (GLUT4) to the plasma membrane / TP53 Regulates Metabolic Genes / Stabilization of p53 / Regulation of RUNX3 expression and activity / negative regulation of protein kinase activity / protein destabilization / cellular response to gamma radiation / RING-type E3 ubiquitin transferase / negative regulation of cysteine-type endopeptidase activity involved in apoptotic process / establishment of protein localization / Oncogene Induced Senescence / Regulation of TP53 Activity through Methylation / response to toxic substance / cellular response to hydrogen peroxide / cellular response to growth factor stimulus / protein polyubiquitination / ubiquitin-protein transferase activity / endocytic vesicle membrane / ubiquitin protein ligase activity / intrinsic apoptotic signaling pathway in response to DNA damage / 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
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 signature. / Zinc finger, RanBP2-type superfamily / Zinc finger, RanBP2-type / 14-3-3 protein sigma / 14-3-3 proteins signature 2. / 14-3-3 protein, conserved site / 14-3-3 proteins signature 1. / 14-3-3 protein / 14-3-3 homologues / 14-3-3 domain / 14-3-3 domain superfamily / 14-3-3 protein / Zinc finger RING-type profile. / Zinc finger, RING-type / Zinc finger, RING/FYVE/PHD-type
Similarity search - Domain/homology
DI(HYDROXYETHYL)ETHER / 14-3-3 protein sigma / E3 ubiquitin-protein ligase Mdm2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / FOURIER SYNTHESIS / Resolution: 1.31 Å
AuthorsRoversi, P. / Ward, J. / Doveston, R. / Kwon, H. / Romartinez Alonso, B.
Funding support United Kingdom, 5items
OrganizationGrant numberCountry
Wellcome Trust204801/Z/16/Z United Kingdom
Engineering and Physical Sciences Research CouncilEP/W015803/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/S019456/1 United Kingdom
Biotechnology and Biological Sciences Research Council (BBSRC)BB/M01116X/1 United Kingdom
Wellcome Trust214090/Z/18/Z United Kingdom
CitationJournal: J.Biol.Chem. / Year: 2024
Title: Characterizing the protein-protein interaction between MDM2 and 14-3-3 sigma ; proof of concept for small molecule stabilization.
Authors: Ward, J.A. / Romartinez-Alonso, B. / Kay, D.F. / Bellamy-Carter, J. / Thurairajah, B. / Basran, J. / Kwon, H. / Leney, A.C. / Macip, S. / Roversi, P. / Muskett, F.W. / Doveston, R.G.
History
DepositionMay 10, 2023Deposition site: PDBE / Processing site: PDBE
Revision 1.0Feb 21, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: 14-3-3 protein sigma
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,6717
Polymers33,3892
Non-polymers2825
Water6,612367
1
A: 14-3-3 protein sigma
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules

A: 14-3-3 protein sigma
B: E3 ubiquitin-protein ligase Mdm2
hetero molecules


Theoretical massNumber of molelcules
Total (without water)67,34314
Polymers66,7784
Non-polymers56510
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4810 Å2
ΔGint-58 kcal/mol
Surface area23630 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.588, 111.824, 62.551
Angle α, β, γ (deg.)90, 90, 90
Int Tables number20
Space group name H-MC2221

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Components

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Protein / Protein/peptide , 2 types, 2 molecules AB

#1: Protein 14-3-3 protein sigma / Epithelial cell marker protein 1 / Stratifin


Mass: 29549.094 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: TEV protease cleavable N-terminal His-tag. Cterm Delta-17 construct
Source: (gene. exp.) Homo sapiens (human) / Gene: SFN, HME1 / Plasmid: pPROEX Htb / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: P31947
#2: Protein/peptide 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: 3839.950 Da / Num. of mol.: 1 / Source method: obtained synthetically
Details: I modified this in order to be able to submit, but please correct the sequence of the peptide: RRRAI(SEP)ETEENSDELSGERQRKRHK(SEP)DSISL
Source: (synth.) Homo sapiens (human)
References: UniProt: Q00987, RING-type E3 ubiquitin transferase

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Non-polymers , 5 types, 372 molecules

#3: Chemical ChemComp-GOL / GLYCEROL / GLYCERIN / PROPANE-1,2,3-TRIOL / Glycerol


Mass: 92.094 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C3H8O3
#4: Chemical ChemComp-PEG / DI(HYDROXYETHYL)ETHER / Diethylene glycol


Mass: 106.120 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O3
#5: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#6: Chemical ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Mg
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 367 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 47.88 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop / pH: 7.5
Details: 1 M HEPES pH 7.4 to 7.6, 0.19 M CaCl2, 30 to 31 % PEG 400, 5 % glycerol
PH range: 7.4 to 7.6

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Data collection

DiffractionMean temperature: 100 K / Ambient temp details: Oxford Cryostream - 800 Series / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I04 / Wavelength: 0.91001 Å
DetectorType: DECTRIS EIGER2 X 16M / Detector: PIXEL / Date: Nov 27, 2021
RadiationMonochromator: double crystal / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.91001 Å / Relative weight: 1
ReflectionResolution: 1.31→1.33 Å / Num. obs: 69740 / % possible obs: 100 % / Redundancy: 13.5 % / CC1/2: 0.998 / Rmerge(I) obs: 0.139 / Rpim(I) all: 0.039 / Rrim(I) all: 0.145 / Net I/σ(I): 9.7
Reflection shellResolution: 1.31→1.33 Å / Redundancy: 13.6 % / Rmerge(I) obs: 3.2 / Mean I/σ(I) obs: 0.5 / Num. unique obs: 3449 / CC1/2: 0.299 / Rpim(I) all: 0.892 / Rrim(I) all: 3.324 / % possible all: 99.7

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Processing

Software
NameVersionClassification
BUSTER2.10.4refinement
xia23.8.dev0data reduction
DIALS3.dev.615-gfee771ddcdata scaling
BUSTER2.10.4phasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.31→18.64 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.961 / SU R Cruickshank DPI: 0.051 / Cross valid method: THROUGHOUT / SU R Blow DPI: 0.051 / SU Rfree Blow DPI: 0.054 / SU Rfree Cruickshank DPI: 0.05
RfactorNum. reflection% reflectionSelection details
Rfree0.2036 3384 -RANDOM
Rwork0.1775 ---
obs0.1788 69663 100 %-
Displacement parametersBiso mean: 22.95 Å2
Baniso -1Baniso -2Baniso -3
1--2.6563 Å20 Å20 Å2
2--0.8142 Å20 Å2
3---1.8421 Å2
Refine analyzeLuzzati coordinate error obs: 0.17 Å
Refinement stepCycle: LAST / Resolution: 1.31→18.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1912 0 16 367 2295
Refine LS restraints
Refine-IDTypeDev idealNumberRestraint functionWeight
X-RAY DIFFRACTIONt_bond_d0.0124203HARMONIC2
X-RAY DIFFRACTIONt_angle_deg1.177639HARMONIC2
X-RAY DIFFRACTIONt_dihedral_angle_d1350SINUSOIDAL2
X-RAY DIFFRACTIONt_gen_planes699HARMONIC5
X-RAY DIFFRACTIONt_it4203HARMONIC10
X-RAY DIFFRACTIONt_chiral_improper_torsion285SEMIHARMONIC5
X-RAY DIFFRACTIONt_ideal_dist_contact4940SEMIHARMONIC4
X-RAY DIFFRACTIONt_omega_torsion4.66
X-RAY DIFFRACTIONt_other_torsion15.66
LS refinement shellResolution: 1.31→1.32 Å
RfactorNum. reflection% reflection
Rfree0.3331 75 -
Rwork0.3468 --
obs0.3461 1394 99.56 %
Refinement TLS params.

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)
10.2805-0.14340.11450.3325-0.12070.3632-0.0430.0402-0.04590.04020.03380.0452-0.04590.04520.0092-0.01880.0081-0.0007-0.0231-0.0059-0.014-23.89-16.66698.323
210.7128-1.75442.908621.20873.01684.54680.07310.0936-0.09970.09360.17640.3592-0.09970.3592-0.24940.02560.01970.01480.03120.04420.0524-14.3893-14.431510.2068
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A-3 - 231
2X-RAY DIFFRACTION1{ A|* }A301 - 302
3X-RAY DIFFRACTION2{ B|* }B164 - 187

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