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- PDB-8ejr: Kelch domain of human KEAP1 bound to Nrf2 linear peptide, Ac-GDPE... -

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Basic information

Entry
Database: PDB / ID: 8ejr
TitleKelch domain of human KEAP1 bound to Nrf2 linear peptide, Ac-GDPETGE-NH2
Components
  • Kelch-like ECH-associated protein 1
  • Linear peptide from Nuclear factor erythroid 2-related factor 2
KeywordsPROTEIN BINDING / Protein interaction / inhibitor / cyclic peptide
Function / homology
Function and homology information


aflatoxin catabolic process / positive regulation of glutathione biosynthetic process / negative regulation of hematopoietic stem cell differentiation / integrated stress response signaling / Regulation of HMOX1 expression and activity / negative regulation of cellular response to hypoxia / NFE2L2 regulating TCA cycle genes / PERK-mediated unfolded protein response / positive regulation of ERAD pathway / regulation of removal of superoxide radicals ...aflatoxin catabolic process / positive regulation of glutathione biosynthetic process / negative regulation of hematopoietic stem cell differentiation / integrated stress response signaling / Regulation of HMOX1 expression and activity / negative regulation of cellular response to hypoxia / NFE2L2 regulating TCA cycle genes / PERK-mediated unfolded protein response / positive regulation of ERAD pathway / regulation of removal of superoxide radicals / regulation of cellular response to oxidative stress / regulation of epidermal cell differentiation / cellular response to laminar fluid shear stress / positive regulation of ubiquitin-dependent protein catabolic process / NFE2L2 regulating ER-stress associated genes / NFE2L2 regulating inflammation associated genes / mediator complex / cellular response to fluid shear stress / cellular response to methionine / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / negative regulation of response to oxidative stress / negative regulation of ferroptosis / negative regulation of cardiac muscle cell apoptotic process / NFE2L2 regulating tumorigenic genes / NFE2L2 regulating anti-oxidant/detoxification enzymes / proteasomal ubiquitin-independent protein catabolic process / Cul3-RING ubiquitin ligase complex / regulation of innate immune response / transcription regulator inhibitor activity / negative regulation of vascular associated smooth muscle cell migration / regulation of embryonic development / centriolar satellite / cellular response to angiotensin / positive regulation of blood vessel endothelial cell migration / positive regulation of blood coagulation / ubiquitin-like ligase-substrate adaptor activity / negative regulation of endothelial cell apoptotic process / cellular response to glucose starvation / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / endoplasmic reticulum unfolded protein response / inclusion body / cellular response to copper ion / reactive oxygen species metabolic process / cellular response to interleukin-4 / cell redox homeostasis / transcription coregulator binding / response to ischemia / regulation of autophagy / actin filament / positive regulation of D-glucose import / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Heme signaling / protein-DNA complex / molecular condensate scaffold activity / positive regulation of neuron projection development / cellular response to hydrogen peroxide / RNA polymerase II transcription regulator complex / positive regulation of angiogenesis / positive regulation of reactive oxygen species metabolic process / disordered domain specific binding / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / cellular response to xenobiotic stimulus / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / cellular response to tumor necrosis factor / Neddylation / midbody / ubiquitin-dependent protein catabolic process / cellular response to oxidative stress / DNA-binding transcription activator activity, RNA polymerase II-specific / cellular response to hypoxia / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / sequence-specific DNA binding / response to oxidative stress / Potential therapeutics for SARS / DNA-binding transcription factor activity, RNA polymerase II-specific / transcription cis-regulatory region binding / Ub-specific processing proteases / protein ubiquitination / inflammatory response / protein domain specific binding / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / centrosome / ubiquitin protein ligase binding / positive regulation of gene expression / regulation of transcription by RNA polymerase II / chromatin / positive regulation of DNA-templated transcription / Golgi apparatus / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm
Similarity search - Function
: / Basic leucine zipper domain, Maf-type / bZIP Maf transcription factor / Transcription factor, Skn-1-like, DNA-binding domain superfamily / Kelch-like ECH-associated protein 1 / : / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch ...: / Basic leucine zipper domain, Maf-type / bZIP Maf transcription factor / Transcription factor, Skn-1-like, DNA-binding domain superfamily / Kelch-like ECH-associated protein 1 / : / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif / Kelch repeat type 1 / Basic-leucine zipper (bZIP) domain signature. / Basic-leucine zipper (bZIP) domain profile. / basic region leucin zipper / Basic-leucine zipper domain / Basic-leucine zipper domain superfamily / Kelch-type beta propeller / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily
Similarity search - Domain/homology
Kelch-like ECH-associated protein 1 / Nuclear factor erythroid 2-related factor 2
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.08 Å
AuthorsMuellers, S.N. / Allen, K.N.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: To Be Published
Title: The benefit of cyclization: a comparison of cyclic and linear peptide inhibitors of the KEAP1/Nrf2 protein-protein interaction
Authors: Muellers, S.N. / Allen, K.N. / Whitty, A.
History
DepositionSep 18, 2022Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 27, 2023Provider: repository / Type: Initial release
Revision 1.1Oct 16, 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

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Assembly

Deposited unit
A: Kelch-like ECH-associated protein 1
B: Kelch-like ECH-associated protein 1
C: Linear peptide from Nuclear factor erythroid 2-related factor 2


Theoretical massNumber of molelcules
Total (without water)74,5263
Polymers74,5263
Non-polymers00
Water5,080282
1
A: Kelch-like ECH-associated protein 1


Theoretical massNumber of molelcules
Total (without water)36,8991
Polymers36,8991
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11900 Å2
MethodPISA
2
B: Kelch-like ECH-associated protein 1
C: Linear peptide from Nuclear factor erythroid 2-related factor 2


Theoretical massNumber of molelcules
Total (without water)37,6272
Polymers37,6272
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1170 Å2
ΔGint0 kcal/mol
Surface area12000 Å2
MethodPISA
Unit cell
Length a, b, c (Å)162.806, 68.909, 77.586
Angle α, β, γ (deg.)90.000, 117.658, 90.000
Int Tables number5
Space group name H-MC121
Space group name HallC2y
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z
#4: -x+1/2,y+1/2,-z
Components on special symmetry positions
IDModelComponents
11B-760-

HOH

21B-796-

HOH

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Components

#1: Protein Kelch-like ECH-associated protein 1 / Cytosolic inhibitor of Nrf2 / INrf2 / Kelch-like protein 19


Mass: 36899.176 Da / Num. of mol.: 2 / Fragment: UNP residues 320-812
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Protein/peptide Linear peptide from Nuclear factor erythroid 2-related factor 2 / NF-E2-related factor 2 / NFE2-related factor 2 / Nrf-2 / HEBP1 / Nuclear factor / erythroid derived 2 / like 2


Mass: 727.698 Da / Num. of mol.: 1 / Source method: obtained synthetically / Source: (synth.) Homo sapiens (human) / References: UniProt: Q16236
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 282 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
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: 2.59 Å3/Da / Density % sol: 52.44 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 1.6 M ammonium sulfate, 100 mM Bis-Tris pH 6.5, 0.8% PEG monomethyl ether (MME) 550

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: NSLS-II / Beamline: 17-ID-2 / Wavelength: 0.977 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Mar 23, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.977 Å / Relative weight: 1
ReflectionResolution: 2.08→29.41 Å / Num. obs: 45416 / % possible obs: 98.96 % / Redundancy: 5 % / Biso Wilson estimate: 30.31 Å2 / CC1/2: 0.971 / Rmerge(I) obs: 0.284 / Rpim(I) all: 0.142 / Rrim(I) all: 0.318 / Net I/σ(I): 9.9
Reflection shellResolution: 2.08→2.154 Å / Redundancy: 4.9 % / Rmerge(I) obs: 0.886 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 4519 / CC1/2: 0.77 / Rpim(I) all: 0.435 / Rrim(I) all: 0.99 / % possible all: 98.41

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
XDSdata reduction
XDSdata scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WFV

5wfv


Resolution: 2.08→29.41 Å / SU ML: 0.264 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 27.172
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2486 1896 4.18 %
Rwork0.2223 43507 -
obs0.2234 45403 99 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 39.49 Å2
Refinement stepCycle: LAST / Resolution: 2.08→29.41 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4340 0 52 282 4674
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00954497
X-RAY DIFFRACTIONf_angle_d1.23646126
X-RAY DIFFRACTIONf_chiral_restr0.0736656
X-RAY DIFFRACTIONf_plane_restr0.0064809
X-RAY DIFFRACTIONf_dihedral_angle_d22.3211590
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.08-2.130.29741350.25753063X-RAY DIFFRACTION98.37
2.13-2.190.26781290.26533065X-RAY DIFFRACTION98.46
2.19-2.250.31431370.25413077X-RAY DIFFRACTION98.59
2.25-2.330.28461370.24953084X-RAY DIFFRACTION98.62
2.33-2.410.29521360.24843084X-RAY DIFFRACTION98.77
2.41-2.510.31751300.2493091X-RAY DIFFRACTION98.93
2.51-2.620.31291330.25463087X-RAY DIFFRACTION99.02
2.62-2.760.30361390.2453108X-RAY DIFFRACTION99.08
2.76-2.930.2491330.23023092X-RAY DIFFRACTION99.23
2.93-3.160.25491380.2293134X-RAY DIFFRACTION99.33
3.16-3.470.25811340.22143113X-RAY DIFFRACTION99.3
3.47-3.980.2131380.20523142X-RAY DIFFRACTION99.48
3.98-5.010.17091350.17273152X-RAY DIFFRACTION99.61
5.01-29.410.2581420.22753215X-RAY DIFFRACTION99.32

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