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

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Basic information

Entry
Database: PDB / ID: 6zey
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


cellular response to carbohydrate stimulus / KEAP1-NFE2L2 pathway / regulation of epidermal cell differentiation / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / centriolar satellite / inclusion body ...cellular response to carbohydrate stimulus / KEAP1-NFE2L2 pathway / regulation of epidermal cell differentiation / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / centriolar satellite / inclusion body / cellular response to interleukin-4 / regulation of autophagy / actin filament / adherens junction / disordered domain specific binding / cellular response to oxidative stress / midbody / ubiquitin-dependent protein catabolic process / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / protein ubiquitination / negative regulation of gene expression / focal adhesion / regulation of DNA-templated transcription / 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 repeat type 1 / Kelch motif / 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 repeat type 1 / Kelch motif / 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-QGZ / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.801 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

Downloads & links

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Assembly

Deposited unit
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)34,1367
Polymers33,3621
Non-polymers7746
Water2,270126
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1030 Å2
ΔGint13 kcal/mol
Surface area11830 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.030, 104.030, 55.992
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 / Dimethyl sulfoxide


Mass: 78.133 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-QGZ / 5-cyclopropyl-1-[3-(phenylsulfonylamino)phenyl]pyrazole-4-carboxylic acid


Mass: 383.421 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C19H17N3O4S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 126 / 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: 2.78 Å3/Da / Density % sol: 55.78 %
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 26, 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: 1.801→52.01 Å / Num. obs: 32103 / % possible obs: 99.98 % / Redundancy: 11.4 % / Biso Wilson estimate: 29.16 Å2 / CC1/2: 1 / Rmerge(I) obs: 0.06105 / Rpim(I) all: 0.01889 / Rrim(I) all: 0.06393 / Net I/σ(I): 21.85
Reflection shellResolution: 1.801→1.865 Å / Redundancy: 11.6 % / Rmerge(I) obs: 0.6814 / Mean I/σ(I) obs: 2.69 / Num. unique obs: 3185 / CC1/2: 0.896 / Rpim(I) all: 0.2081 / Rrim(I) all: 0.7127 / % possible all: 99.97

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Processing

Software
NameVersionClassification
XDSv Jan 26, 2018data reduction
autoPROC1.1.7data scaling
PHASER1.13-2998phasing
PHENIX1.13-2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.801→52.01 Å / SU ML: 0.1593 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 19.4066 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.1876 1694 5.28 %Random
Rwork0.1666 30405 --
obs0.1676 32099 99.98 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 44.76 Å2
Refinement stepCycle: LAST / Resolution: 1.801→52.01 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 47 126 2386
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00492324
X-RAY DIFFRACTIONf_angle_d0.8373164
X-RAY DIFFRACTIONf_chiral_restr0.054329
X-RAY DIFFRACTIONf_plane_restr0.005415
X-RAY DIFFRACTIONf_dihedral_angle_d13.65641349
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.801-1.850.28431210.22582520X-RAY DIFFRACTION100
1.85-1.910.23441410.20972515X-RAY DIFFRACTION99.92
1.91-1.980.21921520.19162521X-RAY DIFFRACTION100
1.98-2.060.19711320.17392516X-RAY DIFFRACTION100
2.06-2.160.20711610.1812506X-RAY DIFFRACTION100
2.16-2.270.19321470.17042531X-RAY DIFFRACTION100
2.27-2.410.22111390.17622529X-RAY DIFFRACTION100
2.41-2.60.19431380.18042517X-RAY DIFFRACTION100
2.6-2.860.20671630.1732512X-RAY DIFFRACTION100
2.86-3.270.18071200.18252566X-RAY DIFFRACTION100
3.27-4.120.18461330.15862565X-RAY DIFFRACTION100
4.12-52.010.15691470.14092607X-RAY DIFFRACTION99.89
Refinement TLS params.

Method: refined / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)Origin x (Å)Origin y (Å)Origin z (Å)
11.69287152173-1.32839702933-0.1979562322442.37219756332-0.4560045768083.51952583674-0.196626589473-0.0568421515576-0.411229715082-0.0451383825250.00796552810660.2432675416940.122876327605-0.01247979621180.1573144235130.250350929407-0.005857844330730.02996152772510.3082889781720.03732696811410.3426136940231.96726402047-47.86600269397.29676270713
21.89951282595-0.222837986856-0.2169278932790.996853675777-0.3730519259130.940366051737-0.0363019646263-0.471526650229-0.4590657446980.197631639842-0.05845483133250.124239814357-0.0293506607460.07551409516290.1016683681520.2739901836340.0003935554966870.01854830829690.4022405635750.04502905337450.3417375827664.75135684387-43.963634688812.0803867076
31.62838532719-0.953088419908-0.1092060642812.50960199557-1.388700208024.084850953810.0389174414064-0.323463976221-0.2624779740380.1181253558720.06650726006770.544188862350.00503816831512-0.394588135266-0.1621179540090.250685809621-0.01106906494750.01439325077410.392429075144-0.005409356365880.361989731394-3.70464271828-38.56457907988.73634666711
42.765110441540.107403020894-0.1023269175351.63108114387-0.5772413411860.8545702167010.005685078885160.08473015841480.309071095458-0.02156215689460.04730178018980.118887118504-0.221884825374-0.019749908048-0.04161562542440.2574358078730.00382977585921-0.02724627442630.26612239172-0.03240494748880.263086038676.49564079487-28.2706895338-0.176288899833
52.26637437013-0.7138384626810.187726771052.055700041260.9083624087982.77190503234-0.02885762203230.5243019849630.350561716797-0.458509836457-0.0332219861182-0.0480545464174-0.1728768296570.006916231319090.06275186347480.308550089693-0.00117725295704-0.03086666118940.3554252678370.03162733497130.26396730937514.1024975317-27.8688028454-8.92652071028
62.29479582101-0.476932904266-0.6401382744762.51937367997-0.1650869841540.8791480138540.03058476898450.396299866833-0.154468719484-0.217710920426-0.02380599448-0.156237775293-0.02891181990920.08314506726470.005289977968610.273995525553-0.008232450017570.01881544027110.36531933613-0.06291942197670.22891427263920.6386645847-40.7902046514-7.31720255557
73.804793534860.6644305894980.6814074036792.229431216651.061258353224.430090912670.0222972257814-0.108469491648-0.6142053392260.1017223650880.0158351143289-0.1834427969630.2110544579870.106538045833-0.04423922952150.2583731969650.018769891195-0.007924017254690.266700785983-0.02050759645760.31209375508216.6928915693-48.86489026541.78525052774
81.619281597540.42359490923-1.297245483031.6358431195-0.6716866845471.10672125051-0.141863165527-0.0468554396647-1.15065807316-0.04811440185820.047407707238-0.04573776745450.1627617029270.06133399879150.1075396081710.267707653043-0.0001266470274280.02507368572510.29068285039-0.0899446614380.44644223535315.085687431-52.9128555932-0.534693497123
92.547326585870.235532590465-0.4428829595481.27392464369-0.3318107487740.149506413951-0.105684834138-0.332117656151-0.5676031786410.406227828446-0.01091961290490.02160499925140.120273520140.04107075455980.09950851336490.33584434550.011764426008-0.02364753025150.3381701313470.0563543167860.38869406645611.0442832316-50.10258985558.11176584361
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 325 through 341 )
2X-RAY DIFFRACTION2chain 'A' and (resid 342 through 377 )
3X-RAY DIFFRACTION3chain 'A' and (resid 378 through 406 )
4X-RAY DIFFRACTION4chain 'A' and (resid 407 through 475 )
5X-RAY DIFFRACTION5chain 'A' and (resid 476 through 500 )
6X-RAY DIFFRACTION6chain 'A' and (resid 501 through 547 )
7X-RAY DIFFRACTION7chain 'A' and (resid 548 through 569 )
8X-RAY DIFFRACTION8chain 'A' and (resid 570 through 589 )
9X-RAY DIFFRACTION9chain 'A' and (resid 590 through 612 )

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