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- PDB-8ejs: Kelch domain of human KEAP1 bound to Nrf2 linear peptide, Ac-(BAl... -

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Basic information

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


positive regulation of glutathione biosynthetic process / aflatoxin catabolic process / negative regulation of hematopoietic stem cell differentiation / non-membrane-bounded organelle / Regulation of HMOX1 expression and activity / integrated stress response signaling / negative regulation of cellular response to hypoxia / NFE2L2 regulating TCA cycle genes / PERK-mediated unfolded protein response / positive regulation of ERAD pathway ...positive regulation of glutathione biosynthetic process / aflatoxin catabolic process / negative regulation of hematopoietic stem cell differentiation / non-membrane-bounded organelle / Regulation of HMOX1 expression and activity / integrated stress response signaling / negative regulation of cellular response to hypoxia / NFE2L2 regulating TCA cycle genes / PERK-mediated unfolded protein response / positive regulation of ERAD pathway / regulation of cellular response to oxidative stress / negative regulation of vascular associated smooth muscle cell migration / regulation of removal of superoxide radicals / regulation of epidermal cell differentiation / cellular response to laminar fluid shear stress / NFE2L2 regulating ER-stress associated genes / positive regulation of ubiquitin-dependent protein catabolic process / mediator complex / NFE2L2 regulating inflammation associated genes / cellular response to fluid shear stress / NFE2L2 regulates pentose phosphate pathway genes / NFE2L2 regulating MDR associated enzymes / cellular response to angiotensin / negative regulation of response to oxidative stress / Nuclear events mediated by NFE2L2 / Regulation of NFE2L2 gene expression / negative regulation of cardiac muscle cell apoptotic process / NFE2L2 regulating anti-oxidant/detoxification enzymes / NFE2L2 regulating tumorigenic genes / Cul3-RING ubiquitin ligase complex / proteasomal ubiquitin-independent protein catabolic process / regulation of innate immune response / regulation of embryonic development / ubiquitin-like ligase-substrate adaptor activity / centriolar satellite / positive regulation of blood vessel endothelial cell migration / positive regulation of blood coagulation / cellular response to interleukin-4 / cellular response to glucose starvation / negative regulation of endothelial cell apoptotic process / negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway / endoplasmic reticulum unfolded protein response / inclusion body / cellular response to copper ion / molecular condensate scaffold activity / cell redox homeostasis / regulation of autophagy / transcription coregulator binding / response to ischemia / positive regulation of glucose import / actin filament / protein-DNA complex / GSK3B and BTRC:CUL1-mediated-degradation of NFE2L2 / Heme signaling / negative regulation of DNA-binding transcription factor 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 / KEAP1-NFE2L2 pathway / disordered domain specific binding / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / cellular response to xenobiotic stimulus / cellular response to tumor necrosis factor / Neddylation / midbody / cellular response to oxidative stress / cellular response to hypoxia / ubiquitin-dependent protein catabolic process / DNA-binding transcription activator activity, RNA polymerase II-specific / proteasome-mediated ubiquitin-dependent protein catabolic process / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / response to oxidative stress / sequence-specific DNA binding / Potential therapeutics for SARS / transcription cis-regulatory region binding / DNA-binding transcription factor activity, RNA polymerase II-specific / Ub-specific processing proteases / protein ubiquitination / inflammatory response / RNA polymerase II cis-regulatory region sequence-specific DNA binding / DNA-binding transcription factor activity / protein domain specific binding / centrosome / ubiquitin protein ligase binding / positive regulation of gene expression / chromatin / regulation of transcription by RNA polymerase II / positive regulation of DNA-templated transcription / Golgi apparatus / endoplasmic reticulum / positive regulation of transcription by RNA polymerase II / DNA binding / nucleoplasm / identical protein binding / nucleus / plasma membrane
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 repeat type 1 / Kelch motif / Basic-leucine zipper (bZIP) domain signature. / Basic-leucine zipper (bZIP) domain profile. / basic region leucin zipper / Basic-leucine zipper domain superfamily / Basic-leucine zipper domain / 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: 2.82 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

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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: Peptide from Nuclear factor erythroid 2-related factor 2


Theoretical massNumber of molelcules
Total (without water)74,5143
Polymers74,5143
Non-polymers00
Water2,306128
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 area11860 Å2
MethodPISA
2
B: Kelch-like ECH-associated protein 1
C: Peptide from Nuclear factor erythroid 2-related factor 2


Theoretical massNumber of molelcules
Total (without water)37,6152
Polymers37,6152
Non-polymers00
Water362
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1060 Å2
ΔGint1 kcal/mol
Surface area11760 Å2
MethodPISA
Unit cell
Length a, b, c (Å)77.690, 68.908, 144.092
Angle α, β, γ (deg.)90.000, 90.851, 90.000
Int Tables number5
Space group name H-MI121
Space group name HallC2y(x,y,-x+z)
Symmetry operation#1: x,y,z
#2: -x,y,-z
#3: x+1/2,y+1/2,z+1/2
#4: -x+1/2,y+1/2,-z+1/2

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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 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: 715.687 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.: 128 / 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: 2.59 Å3/Da / Density % sol: 52.47 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 1.6 M ammonium sulfate, 100 mM Bis-Tris pH 6.5, 0.2-0.8% PEG monomethyl ether (MME) 550

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SSRL / Beamline: BL12-2 / Wavelength: 0.987 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jul 1, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.987 Å / Relative weight: 1
ReflectionResolution: 2.82→39.4 Å / Num. obs: 18329 / % possible obs: 98.46 % / Redundancy: 13.2 % / Biso Wilson estimate: 33.12 Å2 / CC1/2: 0.934 / Rmerge(I) obs: 0.585 / Rpim(I) all: 0.164 / Rrim(I) all: 0.608 / Net I/σ(I): 3.4
Reflection shellResolution: 2.82→2.921 Å / Redundancy: 13 % / Rmerge(I) obs: 0.91 / Mean I/σ(I) obs: 1.8 / Num. unique obs: 1838 / CC1/2: 0.747 / Rpim(I) all: 0.26 / Rrim(I) all: 0.947 / % possible all: 98.87

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Processing

Software
NameVersionClassification
PHENIX1.17.1_3660refinement
HKL-3000data reduction
HKL-3000data scaling
PHENIXphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WFV

5wfv


Resolution: 2.82→39.4 Å / SU ML: 0.302 / Cross valid method: FREE R-VALUE / σ(F): 1.33 / Phase error: 25.1806
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.2656 795 4.34 %
Rwork0.2169 17515 -
obs0.2189 18310 98.57 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 49.54 Å2
Refinement stepCycle: LAST / Resolution: 2.82→39.4 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4340 0 50 128 4518
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00664495
X-RAY DIFFRACTIONf_angle_d0.80466123
X-RAY DIFFRACTIONf_chiral_restr0.0595656
X-RAY DIFFRACTIONf_plane_restr0.004808
X-RAY DIFFRACTIONf_dihedral_angle_d22.4251591
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.82-30.30991320.26372933X-RAY DIFFRACTION99.06
3-3.230.28841310.25272892X-RAY DIFFRACTION98.76
3.23-3.550.26611320.22682881X-RAY DIFFRACTION98.08
3.55-4.070.27841370.21092939X-RAY DIFFRACTION99.48
4.07-5.120.20111260.16922894X-RAY DIFFRACTION98.02
5.12-39.40.29631370.23222976X-RAY DIFFRACTION98.08

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