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- PDB-7ofe: Keap1 kelch domain bound to a small molecule inhibitor of the Kea... -

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Basic information

Entry
Database: PDB / ID: 7ofe
TitleKeap1 kelch domain bound to a small molecule inhibitor of the Keap1-Nrf2 protein-protein interaction
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 / midbody / cellular response to oxidative stress / ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of autophagy / protein ubiquitination / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / 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 / Kelch motif / 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 / Kelch motif / 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-VBQ / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.19 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)32,90811
Polymers31,8881
Non-polymers1,02010
Water4,630257
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1690 Å2
ΔGint-6 kcal/mol
Surface area12370 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.082, 103.082, 55.208
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: 31887.643 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-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-VBQ / 2-[(9-oxidanylidenefluoren-4-yl)carbonylamino]ethanoic acid


Mass: 281.263 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C16H11NO4 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 257 / 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: 2.48 Å3/Da / Density % sol: 50.4 %
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: PETRA III, EMBL c/o DESY / Beamline: P14 (MX2) / Wavelength: 0.979126 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 18, 2019 / Details: Toroidal mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.979126 Å / Relative weight: 1
ReflectionResolution: 1.19→37.67 Å / Num. obs: 106493 / % possible obs: 99.83 % / Redundancy: 13.4 % / Biso Wilson estimate: 12.49 Å2 / CC1/2: 0.999 / CC star: 1 / Rmerge(I) obs: 0.05953 / Rpim(I) all: 0.01667 / Rrim(I) all: 0.06186 / Net I/σ(I): 23.41
Reflection shellResolution: 1.191→1.234 Å / Redundancy: 10.3 % / Rmerge(I) obs: 0.7067 / Mean I/σ(I) obs: 3.81 / Num. unique obs: 10446 / CC1/2: 0.883 / CC star: 0.968 / Rpim(I) all: 0.2328 / Rrim(I) all: 0.7447 / % possible all: 98.58

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Processing

Software
NameVersionClassification
XDSv Mar 15, 2019data reduction
XDSv Mar 15, 2019data scaling
PHASER1.13_2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.19→37.67 Å / SU ML: 0.0849 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 12.7252 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.1498 5326 5 %Random
Rwork0.1303 101158 --
obs0.1312 106484 99.83 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 19.67 Å2
Refinement stepCycle: LAST / Resolution: 1.19→37.67 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2235 0 59 257 2551
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072460
X-RAY DIFFRACTIONf_angle_d1.03463362
X-RAY DIFFRACTIONf_chiral_restr0.0935346
X-RAY DIFFRACTIONf_plane_restr0.0063449
X-RAY DIFFRACTIONf_dihedral_angle_d20.9434893
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.19-1.20.21231700.17383219X-RAY DIFFRACTION95.73
1.2-1.220.21671780.17153380X-RAY DIFFRACTION100
1.22-1.230.1781750.1513326X-RAY DIFFRACTION100
1.23-1.250.15671770.14853369X-RAY DIFFRACTION100
1.25-1.270.17751750.14233352X-RAY DIFFRACTION99.92
1.27-1.280.16291780.13643375X-RAY DIFFRACTION100
1.28-1.30.18231780.13283374X-RAY DIFFRACTION99.94
1.3-1.320.15221760.12633340X-RAY DIFFRACTION100
1.32-1.340.14631770.12353369X-RAY DIFFRACTION100
1.34-1.360.141770.12393374X-RAY DIFFRACTION100
1.36-1.390.15931780.11713364X-RAY DIFFRACTION100
1.39-1.410.14581770.11713371X-RAY DIFFRACTION100
1.41-1.440.1481760.11623343X-RAY DIFFRACTION100
1.44-1.470.13271790.11643393X-RAY DIFFRACTION100
1.47-1.50.15381760.11393353X-RAY DIFFRACTION100
1.5-1.540.14391780.10583387X-RAY DIFFRACTION100
1.54-1.570.12481770.11143357X-RAY DIFFRACTION100
1.57-1.620.12461780.10923374X-RAY DIFFRACTION100
1.62-1.660.15031770.11133377X-RAY DIFFRACTION100
1.66-1.720.13891790.11463393X-RAY DIFFRACTION100
1.72-1.780.1291780.11523374X-RAY DIFFRACTION100
1.78-1.850.11881760.11463348X-RAY DIFFRACTION99.97
1.85-1.930.13241780.11783377X-RAY DIFFRACTION99.92
1.93-2.040.14031780.11393376X-RAY DIFFRACTION100
2.04-2.160.13361790.11743402X-RAY DIFFRACTION100
2.16-2.330.12451780.11793390X-RAY DIFFRACTION100
2.33-2.570.14381790.1333402X-RAY DIFFRACTION100
2.57-2.940.14751800.13813406X-RAY DIFFRACTION99.97
2.94-3.70.17021800.14093422X-RAY DIFFRACTION100
3.7-37.670.17231840.15553471X-RAY DIFFRACTION99.54

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