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- PDB-7of9: Keap1 kelch domain bound to a small molecule fragment -

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Basic information

Entry
Database: PDB / ID: 7of9
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 / Maybridge
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
Chem-VBK / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR190-2014-3710 Denmark
CitationJournal: J.Med.Chem. / Year: 2022
Title: Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery.
Authors: Narayanan, D. / Tran, K.T. / Pallesen, J.S. / Solbak, S.M.O. / Qin, Y. / Mukminova, E. / Luchini, M. / Vasilyeva, K.O. / Gonzalez Chichon, D. / Goutsiou, G. / Poulsen, C. / Haapanen, N. / ...Authors: Narayanan, D. / Tran, K.T. / Pallesen, J.S. / Solbak, S.M.O. / Qin, Y. / Mukminova, E. / Luchini, M. / Vasilyeva, K.O. / Gonzalez Chichon, D. / Goutsiou, G. / Poulsen, C. / Haapanen, N. / Popowicz, G.M. / Sattler, M. / Olagnier, D. / Gajhede, M. / Bach, A.
History
DepositionMay 4, 2021Deposition site: PDBE / Processing site: PDBE
Revision 1.0Nov 2, 2022Provider: repository / Type: Initial release
Revision 1.1Nov 23, 2022Group: 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 31, 2024Group: Data collection / Refinement description
Category: chem_comp_atom / chem_comp_bond / pdbx_initial_refinement_model

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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)33,6103
Polymers33,3621
Non-polymers2472
Water1,820101
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area180 Å2
ΔGint1 kcal/mol
Surface area11970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.340, 104.340, 56.030
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-VBK / [(4S)-6,7-dihydro-4H-thieno[3,2-c]pyran-4-yl]methanamine / 4H,6H,7H-thieno[3,2-c]pyran-4-ylmethanamine / 6,7-dihydro-4H-thieno[3,2-c]pyran-4-ylmethanamine / 12225896


Mass: 169.244 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C8H11NOS / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 101 / 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: 2.57 Å3/Da / Density % sol: 52.3 %
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: 0.9772 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Aug 25, 2018 / Details: Toroidal mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9772 Å / Relative weight: 1
ReflectionResolution: 1.799→52.17 Å / Num. obs: 32391 / % possible obs: 99.5 % / Redundancy: 13.5 % / Biso Wilson estimate: 28.12 Å2 / CC1/2: 0.998 / CC star: 1 / Rmerge(I) obs: 0.1236 / Rpim(I) all: 0.03453 / Rrim(I) all: 0.1285 / Net I/σ(I): 10.87
Reflection shellResolution: 1.799→1.864 Å / Redundancy: 11.1 % / Rmerge(I) obs: 0.8561 / Mean I/σ(I) obs: 2.22 / Num. unique obs: 3207 / CC1/2: 0.597 / CC star: 0.864 / Rpim(I) all: 0.2666 / Rrim(I) all: 0.8976 / % possible all: 99.72

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Processing

Software
NameVersionClassification
DIALS1.9.3data reduction
Aimless0.7.1data scaling
PHASER1.13_2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.8→52.17 Å / SU ML: 0.2227 / Cross valid method: FREE R-VALUE / σ(F): 1.51 / Phase error: 25.2464 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.2247 1703 5.28 %Random
Rwork0.2012 30526 --
obs0.2024 32229 99.47 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 41.7 Å2
Refinement stepCycle: LAST / Resolution: 1.8→52.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 15 101 2329
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0042287
X-RAY DIFFRACTIONf_angle_d0.69483113
X-RAY DIFFRACTIONf_chiral_restr0.0507329
X-RAY DIFFRACTIONf_plane_restr0.0039410
X-RAY DIFFRACTIONf_dihedral_angle_d11.41331321
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.850.35131290.34572526X-RAY DIFFRACTION99.66
1.85-1.910.3571330.34992564X-RAY DIFFRACTION100
1.91-1.980.36171550.37942396X-RAY DIFFRACTION95.58
1.98-2.060.26471250.25032561X-RAY DIFFRACTION100
2.06-2.150.24541660.24712541X-RAY DIFFRACTION100
2.15-2.270.3231400.30942494X-RAY DIFFRACTION98.47
2.27-2.410.25991410.21462544X-RAY DIFFRACTION100
2.41-2.60.21761420.21242551X-RAY DIFFRACTION100
2.6-2.860.23231680.1952524X-RAY DIFFRACTION100
2.86-3.270.23551230.19852612X-RAY DIFFRACTION100
3.27-4.120.19851340.17192579X-RAY DIFFRACTION99.96
4.12-52.170.16671470.13972634X-RAY DIFFRACTION99.93

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