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- PDB-6zf5: Keap1 kelch domain bound to a small molecule inhibitor of the Kea... -

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Basic information

Entry
Database: PDB / ID: 6zf5
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 / 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
Chem-QH8 / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.29 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR190-2014-3710 Denmark
Citation
Journal: 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)35,22419
Polymers33,3621
Non-polymers1,86218
Water3,387188
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area2950 Å2
ΔGint16 kcal/mol
Surface area12470 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.189, 103.189, 54.917
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.: 15 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-QH8 / 1-[3-[(4-butylphenyl)sulfonyl-(2-hydroxy-2-oxoethyl)amino]phenyl]-5-cyclopropyl-pyrazole-4-carboxylic acid


Mass: 497.563 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C25H27N3O6S / 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: 2.67 Å3/Da / Density % sol: 54.03 %
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: 0.976245 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 27, 2019 / Details: KB mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.976245 Å / Relative weight: 1
ReflectionResolution: 1.29→51.59 Å / Num. obs: 82576 / % possible obs: 99.62 % / Redundancy: 18.9 % / Biso Wilson estimate: 15.5 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.04714 / Rpim(I) all: 0.01084 / Rrim(I) all: 0.04839 / Net I/σ(I): 29.81
Reflection shellResolution: 1.295→1.341 Å / Redundancy: 11.1 % / Rmerge(I) obs: 0.6923 / Mean I/σ(I) obs: 2.71 / Num. unique obs: 7943 / CC1/2: 0.913 / Rpim(I) all: 0.2142 / Rrim(I) all: 0.726 / % possible all: 96.37

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Processing

Software
NameVersionClassification
XDSv Mar 15, 2019data reduction
autoPROC1.0.5data scaling
PHASER1.13-2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.29→51.59 Å / SU ML: 0.098 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 17.0373 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.1717 4135 5.01 %Random
Rwork0.1487 78441 --
obs0.1499 82576 99.62 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 25.09 Å2
Refinement stepCycle: LAST / Resolution: 1.29→51.59 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2220 0 105 188 2513
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00812377
X-RAY DIFFRACTIONf_angle_d1.01423227
X-RAY DIFFRACTIONf_chiral_restr0.0887332
X-RAY DIFFRACTIONf_plane_restr0.0061418
X-RAY DIFFRACTIONf_dihedral_angle_d18.579825
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.29-1.310.23971360.22352467X-RAY DIFFRACTION94.04
1.31-1.320.20851210.19752536X-RAY DIFFRACTION97.25
1.32-1.340.23461130.19392577X-RAY DIFFRACTION97.68
1.34-1.360.23131500.17352625X-RAY DIFFRACTION99.96
1.36-1.380.21991490.15172599X-RAY DIFFRACTION99.96
1.38-1.390.15691300.14622607X-RAY DIFFRACTION99.96
1.39-1.410.20651500.13422583X-RAY DIFFRACTION100
1.41-1.440.18321380.14312620X-RAY DIFFRACTION99.93
1.44-1.460.20051410.13922593X-RAY DIFFRACTION100
1.46-1.480.18571260.13432643X-RAY DIFFRACTION99.96
1.48-1.510.17211270.13662607X-RAY DIFFRACTION100
1.51-1.540.17421590.12892587X-RAY DIFFRACTION99.89
1.54-1.560.17291440.13182629X-RAY DIFFRACTION99.96
1.56-1.60.14721110.13042607X-RAY DIFFRACTION100
1.6-1.630.15721320.13492617X-RAY DIFFRACTION100
1.63-1.670.18251160.13072680X-RAY DIFFRACTION100
1.67-1.710.17691710.13672560X-RAY DIFFRACTION100
1.71-1.760.14991460.13492602X-RAY DIFFRACTION100
1.76-1.810.16441530.13392628X-RAY DIFFRACTION100
1.81-1.870.15361150.14162631X-RAY DIFFRACTION100
1.87-1.930.1811380.14052611X-RAY DIFFRACTION100
1.93-2.010.14851450.13462641X-RAY DIFFRACTION99.96
2.01-2.10.16071340.14042625X-RAY DIFFRACTION100
2.1-2.210.14511390.13422641X-RAY DIFFRACTION100
2.21-2.350.15851420.13932628X-RAY DIFFRACTION100
2.35-2.530.16441370.15432633X-RAY DIFFRACTION100
2.53-2.790.18391360.16292662X-RAY DIFFRACTION100
2.79-3.190.19371620.16362608X-RAY DIFFRACTION100
3.19-4.020.16881250.15572673X-RAY DIFFRACTION100
4.02-51.590.1691490.15212721X-RAY DIFFRACTION100

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