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- PDB-6zew: Keap1 kelch domain bound to a small molecule fragment -

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Basic information

Entry
Database: PDB / ID: 6zew
TitleKeap1 kelch domain bound to a small molecule fragment
ComponentsKelch-like ECH-associated protein 1
KeywordsPEPTIDE BINDING PROTEIN / Keap1 / Nrf2 / Oxidative stress / Small molecule complex
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 / 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
7-methoxy-1~{H}-benzotriazole / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.38 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR190-2014-3710 Denmark
CitationJournal: J.Med.Chem. / Year: 2021
Title: Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.
Authors: Pallesen, J.S. / Narayanan, D. / Tran, K.T. / Solbak, S.M.O. / Marseglia, G. / Sorensen, L.M.E. / Hoj, L.J. / Munafo, F. / Carmona, R.M.C. / Garcia, A.D. / Desu, H.L. / Brambilla, R. / ...Authors: Pallesen, J.S. / Narayanan, D. / Tran, K.T. / Solbak, S.M.O. / Marseglia, G. / Sorensen, L.M.E. / Hoj, L.J. / Munafo, F. / Carmona, R.M.C. / Garcia, A.D. / Desu, H.L. / Brambilla, R. / Johansen, T.N. / Popowicz, G.M. / Sattler, M. / Gajhede, M. / Bach, A.
History
DepositionJun 16, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: 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 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)34,23311
Polymers33,3621
Non-polymers87010
Water3,405189
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1680 Å2
ΔGint-1 kcal/mol
Surface area12080 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.715, 103.715, 56.294
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-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-QHB / 7-methoxy-1~{H}-benzotriazole


Mass: 149.150 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C7H7N3O / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 189 / 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: 2.77 Å3/Da / Density % sol: 55.59 %
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: ESRF / Beamline: ID29 / Wavelength: 0.9762 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 8, 2018 / Details: Toroidal Mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.378→44.91 Å / Num. obs: 70870 / % possible obs: 99.98 % / Redundancy: 6.8 % / Biso Wilson estimate: 18.38 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.07747 / Rpim(I) all: 0.03197 / Rrim(I) all: 0.08392 / Net I/σ(I): 10.25
Reflection shellResolution: 1.38→1.43 Å / Redundancy: 6.3 % / Rmerge(I) obs: 0.7667 / Mean I/σ(I) obs: 1.25 / Num. unique obs: 7028 / CC1/2: 0.562 / Rpim(I) all: 0.3299 / Rrim(I) all: 0.836 / % possible all: 99.91

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Processing

Software
NameVersionClassification
xia21.8.5data reduction
xia21.8.5data scaling
PHASER1.13-2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.38→44.91 Å / SU ML: 0.1671 / Cross valid method: FREE R-VALUE / σ(F): 1.49 / Phase error: 19.9541 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.1811 3539 5 %Random
Rwork0.1616 67215 --
obs0.1626 70754 99.8 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.8 Å2
Refinement stepCycle: LAST / Resolution: 1.38→44.91 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 48 189 2450
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00452350
X-RAY DIFFRACTIONf_angle_d0.85783200
X-RAY DIFFRACTIONf_chiral_restr0.0826334
X-RAY DIFFRACTIONf_plane_restr0.0043422
X-RAY DIFFRACTIONf_dihedral_angle_d17.3203838
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.38-1.40.29861490.30852674X-RAY DIFFRACTION99.82
1.4-1.420.34681290.29842691X-RAY DIFFRACTION99.96
1.42-1.440.34511160.28272707X-RAY DIFFRACTION99.96
1.44-1.460.29611400.26892652X-RAY DIFFRACTION100
1.46-1.490.26391420.2572679X-RAY DIFFRACTION100
1.49-1.510.22631430.22232726X-RAY DIFFRACTION99.97
1.51-1.540.23241480.20212622X-RAY DIFFRACTION100
1.54-1.570.22671720.19682695X-RAY DIFFRACTION99.97
1.57-1.60.18621290.18242656X-RAY DIFFRACTION100
1.6-1.640.21621390.17552686X-RAY DIFFRACTION100
1.64-1.670.19071500.1652685X-RAY DIFFRACTION100
1.67-1.720.18971370.15962675X-RAY DIFFRACTION100
1.72-1.760.20311500.14932704X-RAY DIFFRACTION99.96
1.76-1.810.20351320.14222695X-RAY DIFFRACTION99.96
1.81-1.870.18891660.14362661X-RAY DIFFRACTION100
1.87-1.940.251540.21942654X-RAY DIFFRACTION98.8
1.94-2.020.15161330.13552687X-RAY DIFFRACTION100
2.02-2.110.13711240.13842708X-RAY DIFFRACTION100
2.11-2.220.15241270.1322714X-RAY DIFFRACTION100
2.22-2.360.21551210.18372640X-RAY DIFFRACTION96.78
2.36-2.540.16041710.14782656X-RAY DIFFRACTION100
2.54-2.80.17441380.1482729X-RAY DIFFRACTION100
2.8-3.20.19211410.14882705X-RAY DIFFRACTION100
3.2-4.040.17241410.1572736X-RAY DIFFRACTION100
4.04-44.910.14021470.14592778X-RAY DIFFRACTION99.93

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