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

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Basic information

Entry
Database: PDB / ID: 7ofd
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
6-fluoranyl-2-methyl-quinolin-4-ol / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.25 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)34,59115
Polymers33,3621
Non-polymers1,22914
Water3,387188
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2280 Å2
ΔGint-3 kcal/mol
Surface area12620 Å2
Unit cell
Length a, b, c (Å)103.013, 103.013, 55.031
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-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.: 11 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-VBW / 6-fluoranyl-2-methyl-quinolin-4-ol


Mass: 177.175 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H8FNO / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 188 / 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: 2.46 Å3/Da / Density meas: 50.1 Mg/m3 / Density % sol: 51.32 %
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: P13 (MX1) / Wavelength: 0.976246 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 26, 2019 / Details: KB mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976246 Å / Relative weight: 1
ReflectionResolution: 1.249→51.51 Å / Num. obs: 91534 / % possible obs: 99.23 % / Redundancy: 18.2 % / Biso Wilson estimate: 14.23 Å2 / CC1/2: 1 / CC star: 1 / Rmerge(I) obs: 0.06059 / Rpim(I) all: 0.01388 / Rrim(I) all: 0.06219 / Net I/σ(I): 24.73
Reflection shellResolution: 1.249→1.294 Å / Redundancy: 8.6 % / Rmerge(I) obs: 0.5983 / Mean I/σ(I) obs: 2.45 / Num. unique obs: 8560 / CC1/2: 0.875 / CC star: 0.966 / Rpim(I) all: 0.2149 / Rrim(I) all: 0.6375 / % possible all: 93.34

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Processing

Software
NameVersionClassification
XDSv Jan 26, 2018data reduction
Aimless0.7.3data scaling
PHENIX1.13_2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.25→51.51 Å / SU ML: 0.121 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 15.6728 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.1711 4577 5 %Random
Rwork0.1498 86957 --
obs0.1509 91534 99.21 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 20.64 Å2
Refinement stepCycle: LAST / Resolution: 1.25→51.51 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2235 0 67 188 2490
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00652449
X-RAY DIFFRACTIONf_angle_d1.0163343
X-RAY DIFFRACTIONf_chiral_restr0.0886346
X-RAY DIFFRACTIONf_plane_restr0.006443
X-RAY DIFFRACTIONf_dihedral_angle_d19.8525875
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.25-1.260.2881230.2282633X-RAY DIFFRACTION89.6
1.26-1.280.25391580.22716X-RAY DIFFRACTION93.22
1.28-1.290.20991420.17782806X-RAY DIFFRACTION97.07
1.29-1.310.2061590.17022826X-RAY DIFFRACTION97.55
1.31-1.330.18921600.15652904X-RAY DIFFRACTION99.87
1.33-1.340.1891320.14712898X-RAY DIFFRACTION99.41
1.34-1.360.1881340.14022885X-RAY DIFFRACTION99.97
1.36-1.380.16671590.13122946X-RAY DIFFRACTION99.97
1.38-1.410.1541970.13252859X-RAY DIFFRACTION99.97
1.41-1.430.18951470.13332888X-RAY DIFFRACTION100
1.43-1.450.18831800.13722919X-RAY DIFFRACTION100
1.45-1.480.15411510.13132887X-RAY DIFFRACTION99.97
1.48-1.510.17851650.13712899X-RAY DIFFRACTION100
1.51-1.540.16541650.13082933X-RAY DIFFRACTION99.97
1.54-1.570.14981390.1292905X-RAY DIFFRACTION100
1.57-1.610.15251500.12562940X-RAY DIFFRACTION100
1.61-1.650.1531390.12762900X-RAY DIFFRACTION100
1.65-1.690.15091210.132967X-RAY DIFFRACTION100
1.69-1.740.16341420.13142924X-RAY DIFFRACTION100
1.74-1.80.14861860.13122874X-RAY DIFFRACTION100
1.8-1.870.13771390.13662932X-RAY DIFFRACTION100
1.87-1.940.1541310.1382948X-RAY DIFFRACTION100
1.94-2.030.15661310.13522957X-RAY DIFFRACTION100
2.03-2.140.16931760.13832889X-RAY DIFFRACTION100
2.14-2.270.15281460.13652917X-RAY DIFFRACTION100
2.27-2.440.15131650.15262945X-RAY DIFFRACTION100
2.44-2.690.1861950.162892X-RAY DIFFRACTION100
2.69-3.080.18291360.16442991X-RAY DIFFRACTION100
3.08-3.880.16971530.16482955X-RAY DIFFRACTION100
3.88-51.510.18831560.16153022X-RAY DIFFRACTION100

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