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

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Basic information

Entry
Database: PDB / ID: 9hww
TitleCrystal structure of the Keap1 Kelch domain in complex with the small molecule UCAB#1032 at 1.61 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 / midbody / ubiquitin-dependent protein catabolic process / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / protein ubiquitination / regulation of autophagy / regulation of DNA-templated transcription / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / identical protein binding / cytosol / cytoplasm
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: 1.61 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)34,62711
Polymers33,3621
Non-polymers1,26410
Water2,720151
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1230 Å2
ΔGint-31 kcal/mol
Surface area12490 Å2
Unit cell
Length a, b, c (Å)103.337, 103.337, 55.025
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

#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
#2: Chemical ChemComp-A1IX0 / (3~{S})-3-[7-[2-(cyclohexylamino)-2-oxidanylidene-ethoxy]naphthalen-2-yl]-3-(2,3-dihydro-1,4-benzodioxin-6-yl)propanoic acid


Mass: 489.560 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C29H31NO6 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 151 / Source method: isolated from a natural source / Formula: H2O
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: 2.68 Å3/Da / Density % sol: 54.1 %
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: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 23, 2022
RadiationMonochromator: Si (111), double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.61→46.87 Å / Num. obs: 43316 / % possible obs: 99.7 % / Redundancy: 20.7 % / Biso Wilson estimate: 20.45 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.244 / Rpim(I) all: 0.055 / Rrim(I) all: 0.25 / Χ2: 0.89 / Net I/σ(I): 14.6 / Num. measured all: 898388
Reflection shellResolution: 1.61→1.67 Å / % possible obs: 98.9 % / Redundancy: 20.8 % / Rmerge(I) obs: 2.285 / Num. measured all: 87260 / Num. unique obs: 4197 / CC1/2: 0.612 / Rpim(I) all: 0.507 / Rrim(I) all: 2.341 / Χ2: 0.68 / Net I/σ(I) obs: 1.3

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Processing

Software
NameVersionClassification
XDS20220604data reduction
Aimless0.7.9data scaling
PHASER2.8.3phasing
PHENIX1.20.1_4487refinement
PDB_EXTRACTdata extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.61→44.75 Å / SU ML: 0.2182 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 18.6602
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1966 2131 4.92 %
Rwork0.1646 41163 -
obs0.166 43294 99.71 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 24.97 Å2
Refinement stepCycle: LAST / Resolution: 1.61→44.75 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2226 0 76 151 2453
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00952457
X-RAY DIFFRACTIONf_angle_d1.06333361
X-RAY DIFFRACTIONf_chiral_restr0.072346
X-RAY DIFFRACTIONf_plane_restr0.0097443
X-RAY DIFFRACTIONf_dihedral_angle_d7.7917372
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.61-1.650.34621510.33722709X-RAY DIFFRACTION99.37
1.65-1.690.28531190.28512713X-RAY DIFFRACTION99.09
1.69-1.740.25081800.22772688X-RAY DIFFRACTION99.31
1.74-1.790.21141600.19752698X-RAY DIFFRACTION99.44
1.79-1.840.20661470.17692732X-RAY DIFFRACTION99.52
1.84-1.910.1981290.18912743X-RAY DIFFRACTION99.69
1.91-1.990.21811730.1662700X-RAY DIFFRACTION99.76
1.99-2.080.14711240.13582741X-RAY DIFFRACTION99.83
2.08-2.190.1731430.13742753X-RAY DIFFRACTION99.9
2.19-2.320.19351600.14372719X-RAY DIFFRACTION99.86
2.32-2.50.18721250.14772768X-RAY DIFFRACTION99.97
2.5-2.750.18631430.1662769X-RAY DIFFRACTION100
2.75-3.150.15611030.16322801X-RAY DIFFRACTION99.97
3.15-3.970.21491240.15592801X-RAY DIFFRACTION100
3.97-44.750.19161500.15872828X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / 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)
10.2643856294650.1869237520680.1340924866850.441519708498-0.370542312170.345156979481-0.09609630378020.1095444723310.1455096830340.2900818054890.03382603913-0.368575192385-0.0121527707936-0.018693258049-0.01440502886260.2179055825190.0312914042993-0.03450229343410.188362327132-0.02746537534250.23568455383939.364555882826.03683119436.76703186032
20.448435113934-0.1678212336030.1914175249220.315784795596-0.3026041648360.423299478709-0.0538255100835-0.02398206772480.03389549816370.2534572471770.0263982508751-0.2731568959370.001491732291820.0040815456844-0.01062904240830.2505507920940.0429778204644-0.04699434579810.180369660881-0.01562658391270.21228009305635.19213165325.815399183511.1118840286
30.7975220453420.4853530124490.735941533780.9045731990350.04032141480510.5223875656710.0487339898845-0.0517607491658-0.2394432346390.1898800298250.120961352944-0.2214139992430.09034551258830.08014897010110.1370150567790.214424433110.0488405081674-0.03427754732990.153217918055-0.006686030026730.18213607348334.345501881116.01929910568.75413272702
40.525187666304-0.1025457321040.4730446700840.487607242977-0.002145939782640.2943526226940.0610839607454-0.0401818206683-0.1204588780.07935822500010.0345522561890.05738790658740.0451060498461-0.03056670025040.0174505442910.1670497180240.01515907685210.0284616291670.132711295242-0.003190541495280.1600487984221.933001967816.24215871950.440957576383
50.8554218820930.3131897084240.1523764559860.889096928999-0.357942452650.553894410945-0.00186119675780.05772295921660.0269876481033-0.124203888594-0.006002319421520.1849163009720.00285659027369-0.0115673858717-0.004344830184670.1459438472810.01873193813240.01720732028330.145868757466-0.007273262785960.14889373646419.124600294229.0074053834-7.36515554481
60.2078897232250.1963422425370.3154701907950.789183189474-0.05168287045020.387893240907-0.1428543115510.1409269926720.0738621094372-0.1241022605640.082190239330.0235371299745-0.0585137179520.0656555934374-0.04049461414340.152891393753-0.001717431180120.03347807275080.1608460106140.02995788314650.14011058345325.479403828238.9030630349-10.0980475871
70.4595236393070.1263498962950.5543536052870.696696081227-0.2617028902120.697946662243-0.05395360609560.08274333523290.1338985543850.0902697973116-0.0396361221086-0.287788253143-0.1402883023310.1754376161544.7128260783E-50.1775426617070.001099207868980.008463693679830.1733878575180.01250905380130.1764194541435.664056940138.9146097472-0.285886472089
80.4417811147230.3895840746410.2213305694590.5869986493910.2647473334630.152981309242-0.00526728514519-0.160410388089-0.03286582211540.332741389264-0.0567226314846-0.176736399674-0.06150075377410.129080929590.0001865856666040.232945486518-0.00209419665935-0.03430152033570.208593156949-0.01266816003450.19630660904837.479880078734.43883063757.58082175888
Refinement TLS group

Refine-ID: X-RAY DIFFRACTION / Auth asym-ID: A / Label asym-ID: A

IDRefine TLS-IDSelection detailsAuth seq-IDLabel seq-ID
11chain 'A' and (resid 324 through 341 )324 - 3411 - 18
22chain 'A' and (resid 342 through 377 )342 - 37719 - 54
33chain 'A' and (resid 378 through 406 )378 - 40655 - 83
44chain 'A' and (resid 407 through 453 )407 - 45384 - 130
55chain 'A' and (resid 454 through 522 )454 - 522131 - 199
66chain 'A' and (resid 523 through 547 )523 - 547200 - 224
77chain 'A' and (resid 548 through 589 )548 - 589225 - 266
88chain 'A' and (resid 590 through 613 )590 - 613267 - 290

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