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- PDB-8bi7: Binary structure of 14-3-3s and PKR phosphopeptide -

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Basic information

Entry
Database: PDB / ID: 8bi7
TitleBinary structure of 14-3-3s and PKR phosphopeptide
Components
  • 14-3-3 protein sigma
  • PKR phosphopeptide
KeywordsPEPTIDE BINDING PROTEIN / 14-3-3 / hub-protein / phosphopeptide
Function / homology
Function and homology information


Inhibition of PKR / regulation of NLRP3 inflammasome complex assembly / eukaryotic translation initiation factor 2alpha kinase activity / response to interferon-alpha / negative regulation of osteoblast proliferation / regulation of hematopoietic progenitor cell differentiation / positive regulation of stress-activated MAPK cascade / protein phosphatase regulator activity / SUMOylation of immune response proteins / regulation of hematopoietic stem cell proliferation ...Inhibition of PKR / regulation of NLRP3 inflammasome complex assembly / eukaryotic translation initiation factor 2alpha kinase activity / response to interferon-alpha / negative regulation of osteoblast proliferation / regulation of hematopoietic progenitor cell differentiation / positive regulation of stress-activated MAPK cascade / protein phosphatase regulator activity / SUMOylation of immune response proteins / regulation of hematopoietic stem cell proliferation / regulation of hematopoietic stem cell differentiation / regulation of translational initiation / negative regulation of viral genome replication / regulation of epidermal cell division / protein kinase C inhibitor activity / positive regulation of epidermal cell differentiation / keratinocyte development / keratinization / regulation of cell-cell adhesion / cAMP/PKA signal transduction / Regulation of localization of FOXO transcription factors / keratinocyte proliferation / phosphoserine residue binding / Activation of BAD and translocation to mitochondria / negative regulation of keratinocyte proliferation / establishment of skin barrier / negative regulation of protein localization to plasma membrane / Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex / SARS-CoV-2 targets host intracellular signalling and regulatory pathways / negative regulation of protein kinase activity / negative regulation of stem cell proliferation / endoplasmic reticulum unfolded protein response / positive regulation of chemokine production / SARS-CoV-1 targets host intracellular signalling and regulatory pathways / RHO GTPases activate PKNs / positive regulation of protein localization / antiviral innate immune response / positive regulation of cell adhesion / cellular response to amino acid starvation / protein sequestering activity / protein export from nucleus / negative regulation of innate immune response / TP53 Regulates Transcription of Genes Involved in G2 Cell Cycle Arrest / release of cytochrome c from mitochondria / positive regulation of cytokine production / positive regulation of protein export from nucleus / stem cell proliferation / TP53 Regulates Metabolic Genes / non-membrane spanning protein tyrosine kinase activity / Translocation of SLC2A4 (GLUT4) to the plasma membrane / non-specific protein-tyrosine kinase / positive regulation of non-canonical NF-kappaB signal transduction / positive regulation of NF-kappaB transcription factor activity / PKR-mediated signaling / Evasion by RSV of host interferon responses / ISG15 antiviral mechanism / response to virus / intrinsic apoptotic signaling pathway in response to DNA damage / Interferon alpha/beta signaling / kinase activity / intracellular protein localization / double-stranded RNA binding / regulation of protein localization / protein autophosphorylation / positive regulation of cell growth / defense response to virus / protein phosphorylation / non-specific serine/threonine protein kinase / protein kinase activity / regulation of cell cycle / negative regulation of translation / positive regulation of MAPK cascade / ribosome / cadherin binding / translation / negative regulation of cell population proliferation / protein serine kinase activity / protein serine/threonine kinase activity / protein kinase binding / negative regulation of apoptotic process / perinuclear region of cytoplasm / negative regulation of transcription by RNA polymerase II / signal transduction / extracellular space / RNA binding / extracellular exosome / nucleoplasm / ATP binding / identical protein binding / nucleus / membrane / cytoplasm / cytosol
Similarity search - Function
EIF2AK2, first double-stranded RNA binding domain / EIF2AK2, second double-stranded RNA binding domain / : / Double-stranded RNA binding motif / Double-stranded RNA binding motif / 14-3-3 domain / Delta-Endotoxin; domain 1 / 14-3-3 protein sigma / Double stranded RNA-binding domain (dsRBD) profile. / Double-stranded RNA-binding domain ...EIF2AK2, first double-stranded RNA binding domain / EIF2AK2, second double-stranded RNA binding domain / : / Double-stranded RNA binding motif / Double-stranded RNA binding motif / 14-3-3 domain / Delta-Endotoxin; domain 1 / 14-3-3 protein sigma / Double stranded RNA-binding domain (dsRBD) profile. / Double-stranded RNA-binding domain / 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 / Serine/threonine-protein kinase, active site / Serine/Threonine protein kinases active-site signature. / Protein kinase domain / Serine/Threonine protein kinases, catalytic domain / Protein kinase, ATP binding site / Protein kinases ATP-binding region signature. / Protein kinase domain profile. / Protein kinase domain / Protein kinase-like domain superfamily / Up-down Bundle / Mainly Alpha
Similarity search - Domain/homology
Interferon-induced, double-stranded RNA-activated protein kinase / 14-3-3 protein sigma
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsSomsen, B.A. / Ottmann, C.
Funding support Netherlands, 1items
OrganizationGrant numberCountry
Netherlands Organisation for Scientific Research (NWO)711.017.014 Netherlands
CitationJournal: J.Am.Chem.Soc. / Year: 2023
Title: Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERR gamma Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach.
Authors: Somsen, B.A. / Schellekens, R.J.C. / Verhoef, C.J.A. / Arkin, M.R. / Ottmann, C. / Cossar, P.J. / Brunsveld, L.
History
DepositionNov 1, 2022Deposition site: PDBE / Processing site: PDBE
Revision 1.0Mar 29, 2023Provider: repository / Type: Initial release
Revision 1.1Apr 5, 2023Group: Database references / Category: citation
Item: _citation.journal_volume / _citation.page_first / _citation.page_last
Revision 1.2Feb 7, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model
Revision 1.3Nov 20, 2024Group: Structure summary / Category: pdbx_entry_details / pdbx_modification_feature / Item: _pdbx_entry_details.has_protein_modification

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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: PKR phosphopeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)28,0536
Polymers27,9552
Non-polymers974
Water5,945330
1
A: 14-3-3 protein sigma
B: PKR phosphopeptide
hetero molecules

A: 14-3-3 protein sigma
B: PKR phosphopeptide
hetero molecules


Theoretical massNumber of molelcules
Total (without water)56,10512
Polymers55,9114
Non-polymers1948
Water724
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
crystal symmetry operation4_555x,-y,-z1
Buried area4500 Å2
ΔGint-47 kcal/mol
Surface area23710 Å2
MethodPISA
Unit cell
Length a, b, c (Å)82.685, 112.465, 62.647
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number20
Space group name H-MC2221
Components on special symmetry positions
IDModelComponents
11A-301-

MG

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Components

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


Mass: 26542.914 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Details: GAMGS at the beginning (-5 to -1) are part of the expression tag
Source: (gene. exp.) Homo sapiens (human) / Gene: SFN, HME1 / Production host: Escherichia coli (E. coli) / References: UniProt: P31947
#2: Protein/peptide PKR phosphopeptide / Interferon-induced / double-stranded RNA-activated protein kinase / Eukaryotic translation ...Interferon-induced / double-stranded RNA-activated protein kinase / Eukaryotic translation initiation factor 2-alpha kinase 2 / eIF-2A protein kinase 2 / Interferon-inducible RNA-dependent protein kinase / P1/eIF-2A protein kinase / Protein kinase RNA-activated / PKR / Protein kinase R / Tyrosine-protein kinase EIF2AK2 / p68 kinase


Mass: 1412.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human)
References: UniProt: P19525, non-specific serine/threonine protein kinase, non-specific protein-tyrosine kinase
#3: Chemical
ChemComp-MG / MAGNESIUM ION


Mass: 24.305 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: Mg
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 330 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN
Has protein modificationY

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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: 2.66 Å3/Da / Density % sol: 53.82 %
Crystal growTemperature: 277 K / Method: vapor diffusion, sitting drop
Details: 0.095 M Hepes pH 7.1, 0.19 M CaCl2, 25% PEG400, 5% glycerol

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: PETRA III, DESY / Beamline: P11 / Wavelength: 1.0332 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 6, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0332 Å / Relative weight: 1
ReflectionResolution: 1.4→45.64 Å / Num. obs: 742644 / % possible obs: 99.7 % / Redundancy: 12.9 % / CC1/2: 0.999 / Net I/σ(I): 36.4
Reflection shellResolution: 1.4→1.43 Å / Mean I/σ(I) obs: 7.1 / Num. unique obs: 33081 / CC1/2: 0.984

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Processing

Software
NameVersionClassification
PHENIX1.20.1_4487refinement
PDB_EXTRACT3.27data extraction
XDSdata reduction
Aimlessdata scaling
MOLREPphasing
REFMAC5.8.0267refinement
Cootmodel building
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 6y1d

6y1d


Resolution: 1.4→45.64 Å / SU ML: 0.12 / Cross valid method: THROUGHOUT / σ(F): 1.33 / Phase error: 17.44 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1882 5523 5.02 %
Rwork0.1704 --
obs0.1713 109989 99.24 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.4→45.64 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1883 0 4 330 2217
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0062010
X-RAY DIFFRACTIONf_angle_d0.8912725
X-RAY DIFFRACTIONf_dihedral_angle_d5.392292
X-RAY DIFFRACTIONf_chiral_restr0.066300
X-RAY DIFFRACTIONf_plane_restr0.009362
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.20662040.21463314X-RAY DIFFRACTION96
1.42-1.430.18341460.18393483X-RAY DIFFRACTION99
1.43-1.450.26211890.24453513X-RAY DIFFRACTION99
1.45-1.470.21591550.19283520X-RAY DIFFRACTION99
1.47-1.490.20981760.21013495X-RAY DIFFRACTION99
1.49-1.510.17321690.16313481X-RAY DIFFRACTION100
1.51-1.530.28872010.25163402X-RAY DIFFRACTION96
1.53-1.550.15441840.16153476X-RAY DIFFRACTION100
1.55-1.580.16852050.15113490X-RAY DIFFRACTION100
1.58-1.60.15132000.14393456X-RAY DIFFRACTION100
1.6-1.630.16291730.14473505X-RAY DIFFRACTION100
1.63-1.660.16651840.14523525X-RAY DIFFRACTION100
1.66-1.690.15591910.14633510X-RAY DIFFRACTION100
1.69-1.730.17321820.15893473X-RAY DIFFRACTION100
1.73-1.770.18922050.1673488X-RAY DIFFRACTION100
1.77-1.810.20941910.17563498X-RAY DIFFRACTION100
1.81-1.850.24071870.18263502X-RAY DIFFRACTION100
1.85-1.90.16992000.18923472X-RAY DIFFRACTION99
1.9-1.960.25091870.20883429X-RAY DIFFRACTION98
1.96-2.020.2221760.1693518X-RAY DIFFRACTION100
2.02-2.090.18591850.17473449X-RAY DIFFRACTION99
2.09-2.180.19861820.15673523X-RAY DIFFRACTION100
2.18-2.280.1631820.17633388X-RAY DIFFRACTION97
2.28-2.40.17041840.16413509X-RAY DIFFRACTION100
2.4-2.550.19691940.16553495X-RAY DIFFRACTION100
2.55-2.740.18751880.16873506X-RAY DIFFRACTION100
2.74-3.020.20051780.18053508X-RAY DIFFRACTION100
3.02-3.460.18442010.16563482X-RAY DIFFRACTION100
3.46-4.350.1671640.14923515X-RAY DIFFRACTION99
4.35-45.640.17711600.16943541X-RAY DIFFRACTION100

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