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- PDB-9hwr: Crystal structure of the Keap1 Kelch domain in complex with the s... -

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Basic information

Entry
Database: PDB / ID: 9hwr
TitleCrystal structure of the Keap1 Kelch domain in complex with the small molecule UCAB#827 at 1.40 Angstrom resolution
ComponentsKelch-like ECH-associated protein 1
KeywordsPEPTIDE BINDING PROTEIN / Keap1 / Nrf2 / Oxidative stress / Inhibitor
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body ...regulation of epidermal cell differentiation / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body / cellular response to interleukin-4 / actin filament / centriolar satellite / disordered domain specific binding / cellular response to oxidative stress / ubiquitin-dependent protein catabolic process / midbody / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / regulation of autophagy / protein ubiquitination / regulation of DNA-templated transcription / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Kelch-like ECH-associated protein 1 / : / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch motif / Kelch / Kelch repeat type 1 / Kelch-type beta propeller ...Kelch-like ECH-associated protein 1 / : / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch motif / Kelch / Kelch repeat type 1 / 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
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.4 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR366-2021-270 Denmark
CitationJournal: Angew.Chem.Int.Ed.Engl. / Year: 2025
Title: Fragment-Based Drug Discovery of Novel High-affinity, Selective, and Anti-inflammatory Inhibitors of the Keap1-Nrf2 Protein-Protein Interaction.
Authors: Lin, C. / Narayanan, D. / Barreca, M. / Poulsen, C. / da Costa, L.S. / Chen, X. / Wichman, K.G. / Charley, C.A. / Lindsay, J.L. / Dezfouli, M. / Vlissari, D. / Mortensen, T.S. / Chan, C.B. / ...Authors: Lin, C. / Narayanan, D. / Barreca, M. / Poulsen, C. / da Costa, L.S. / Chen, X. / Wichman, K.G. / Charley, C.A. / Lindsay, J.L. / Dezfouli, M. / Vlissari, D. / Mortensen, T.S. / Chan, C.B. / Wang, J. / Richardson, W. / Manning, C.E. / Chen, Z. / Zang, J. / Kack, H. / Gajhede, M. / Bullock, A.N. / Blake, D.J. / Olagnier, D. / Bach, A.
History
DepositionJan 6, 2025Deposition site: PDBE / Processing site: PDBE
Revision 1.0Sep 3, 2025Provider: repository / Type: Initial release
Revision 1.1Oct 1, 2025Group: 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
Revision 1.2Oct 8, 2025Group: Database references / Category: citation / citation_author
Item: _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

Deposited unit
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,58525
Polymers33,3621
Non-polymers2,22224
Water4,738263
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3980 Å2
ΔGint-51 kcal/mol
Surface area12820 Å2
Unit cell
Length a, b, c (Å)103.178, 103.178, 54.989
Angle α, β, γ (deg.)90.000, 90.000, 120.000
Int Tables number169
Space group name H-MP61
Space group name HallP61
Symmetry operation#1: x,y,z
#2: x-y,x,z+1/6
#3: y,-x+y,z+5/6
#4: -y,x-y,z+1/3
#5: -x+y,-x,z+2/3
#6: -x,-y,z+1/2

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 33362.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Keap1, Inrf2, Kiaa0132
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9Z2X8

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Non-polymers , 5 types, 287 molecules

#2: Chemical ChemComp-A1IX2 / 1-[3-[2-(cyclohexylamino)-2-oxidanylidene-ethoxy]phenyl]piperidine-4-carboxylic acid


Mass: 360.447 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C20H28N2O4 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#4: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#5: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 16 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 263 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 53.74 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.5 M AMMONIUM SULFATE, 0.1 M SODIUM CITRATE TRIBASIC DIHYDRATE PH 5.6 AND 1.0 M LITHIUM SULFATE MONOHYDRATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 28, 2022
RadiationMonochromator: Si (111), double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.4→46.83 Å / Num. obs: 65280 / % possible obs: 99.5 % / Redundancy: 17.9 % / Biso Wilson estimate: 11.72 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.118 / Rpim(I) all: 0.028 / Rrim(I) all: 0.121 / Χ2: 0.99 / Net I/σ(I): 20.4 / Num. measured all: 1167704
Reflection shellResolution: 1.4→1.43 Å / % possible obs: 93.1 % / Redundancy: 7.9 % / Rmerge(I) obs: 1.088 / Num. measured all: 24067 / Num. unique obs: 3043 / CC1/2: 0.731 / Rpim(I) all: 0.39 / Rrim(I) all: 1.161 / Χ2: 1.07 / Net I/σ(I) obs: 2.7

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Processing

Software
NameVersionClassification
XDS20230630data reduction
Aimless0.7.7data scaling
PHASER2.8.3phasing
PHENIX1.20.1_4487refinement
PDB_EXTRACTV4.2data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.4→44.68 Å / SU ML: 0.1075 / Cross valid method: FREE R-VALUE / σ(F): 0.66 / Phase error: 16.1155
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1581 3206 4.91 %
Rwork0.1315 62023 -
obs0.1328 65229 99.53 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 16.34 Å2
Refinement stepCycle: LAST / Resolution: 1.4→44.68 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2246 0 121 263 2630
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00752540
X-RAY DIFFRACTIONf_angle_d1.08093471
X-RAY DIFFRACTIONf_chiral_restr0.0971355
X-RAY DIFFRACTIONf_plane_restr0.0099456
X-RAY DIFFRACTIONf_dihedral_angle_d6.9155384
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.4-1.420.21661170.18012543X-RAY DIFFRACTION92.81
1.42-1.440.25431480.16272607X-RAY DIFFRACTION97.45
1.44-1.470.19661160.14112708X-RAY DIFFRACTION99.61
1.47-1.490.17821530.13472679X-RAY DIFFRACTION99.82
1.49-1.520.17811200.13492737X-RAY DIFFRACTION99.97
1.52-1.550.19941340.12442657X-RAY DIFFRACTION99.96
1.55-1.580.16951520.11312709X-RAY DIFFRACTION99.97
1.58-1.620.18041290.11582688X-RAY DIFFRACTION99.93
1.62-1.650.15261480.11132692X-RAY DIFFRACTION99.96
1.65-1.70.15091350.11492714X-RAY DIFFRACTION99.93
1.7-1.740.14781320.11162681X-RAY DIFFRACTION100
1.74-1.790.15291530.11432684X-RAY DIFFRACTION100
1.79-1.850.15841350.10872703X-RAY DIFFRACTION100
1.85-1.920.14691610.1122686X-RAY DIFFRACTION100
1.92-1.990.13721300.10852707X-RAY DIFFRACTION100
1.99-2.080.14581310.11062721X-RAY DIFFRACTION100
2.08-2.190.15381250.11282729X-RAY DIFFRACTION100
2.19-2.330.14611440.11772696X-RAY DIFFRACTION100
2.33-2.510.1461280.12642750X-RAY DIFFRACTION100
2.51-2.760.13861350.14482711X-RAY DIFFRACTION100
2.76-3.160.14281530.14182722X-RAY DIFFRACTION100
3.16-3.980.1691450.13892741X-RAY DIFFRACTION100
3.99-44.680.16321820.16172758X-RAY DIFFRACTION99.93

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