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- PDB-6zf2: Keap1 kelch domain bound to a small molecule inhibitor of the Kea... -

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Basic information

Entry
Database: PDB / ID: 6zf2
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-QJ5 / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.2 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)34,1967
Polymers33,3621
Non-polymers8346
Water19811
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area940 Å2
ΔGint2 kcal/mol
Surface area11900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)104.044, 104.044, 53.770
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


Mass: 78.133 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: SO4
#4: Chemical ChemComp-QJ5 / 5-cyclopropyl-1-[3-[(4-propylphenyl)sulfonylamino]phenyl]pyrazole-4-carboxylic acid


Mass: 425.501 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H23N3O4S / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 11 / 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: 2.66 Å3/Da / Density % sol: 53.8 %
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: 0.980201 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Mar 23, 2019 / Details: KB mirrors
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.980201 Å / Relative weight: 1
ReflectionResolution: 2.2→46.17 Å / Num. obs: 15811 / % possible obs: 92.74 % / Redundancy: 2.6 % / Biso Wilson estimate: 40.54 Å2 / CC1/2: 0.996 / Rmerge(I) obs: 0.05615 / Rpim(I) all: 0.04098 / Rrim(I) all: 0.06986 / Net I/σ(I): 11.82
Reflection shellResolution: 2.203→2.282 Å / Redundancy: 2.6 % / Rmerge(I) obs: 0.4506 / Mean I/σ(I) obs: 2.1 / Num. unique obs: 1624 / CC1/2: 0.861 / Rpim(I) all: 0.328 / Rrim(I) all: 0.5601 / % possible all: 95.75

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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: 2.2→46.17 Å / SU ML: 0.303 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 33.8444 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.237 768 4.88 %Random
Rwork0.2069 14971 --
obs0.2085 15739 92.74 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 60 Å2
Refinement stepCycle: LAST / Resolution: 2.2→46.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 51 11 2275
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00262352
X-RAY DIFFRACTIONf_angle_d0.66693209
X-RAY DIFFRACTIONf_chiral_restr0.0493333
X-RAY DIFFRACTIONf_plane_restr0.0038422
X-RAY DIFFRACTIONf_dihedral_angle_d11.22871368
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2-2.370.35021450.33222990X-RAY DIFFRACTION93.05
2.37-2.610.34561540.29312963X-RAY DIFFRACTION92.69
2.61-2.990.28431720.24163038X-RAY DIFFRACTION94.5
2.99-3.770.27041420.21622980X-RAY DIFFRACTION92.48
3.77-46.170.16591550.15553000X-RAY DIFFRACTION91.03
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)
12.11157035193-2.08488051931.545619718344.103690057260.8241686810774.05413112188-0.107034949922-0.4061622449481.02716637506-0.158445398711-0.243096139019-0.38814837234-0.6802873884220.3272130868670.3128418834950.434396926007-0.0142952053579-0.1160262898230.404787059484-0.08147155351870.8102063497-1.9294116542147.74765800257.61409831046
22.71964411784-0.4967492485721.071169359291.841307173371.221442410822.17419778864-0.100990408954-0.4546773913610.6616022223690.2428464008090.0681618407205-0.346497534202-0.0940422191654-0.04298490106070.037367054860.3479985107530.0279549391647-0.05404457443460.433822591437-0.04955050517210.497085988858-1.9056948933238.32007243048.95167302184
32.847485929320.445087158837-0.2571622798342.282461551840.2226007667193.35561412369-0.105724998808-0.12161031544-0.274323025092-0.1229929679310.0385899929297-0.4544117662170.7195624564620.1139912424910.113653826710.3416090671070.0680764255923-0.038591510130.3604293648930.06057124941020.350092753323-1.8281324010325.54759695542.27193083642
41.76833731742-0.133917072112-0.1108989391812.743073357370.1638049802862.078325064450.08559307594820.606726128086-0.0091978043708-0.243990984438-0.1347452474880.3846723213570.04300739104590.005644211157270.1248500206230.3351518998090.0106311162627-0.03734975672680.4531748115890.0433299820610.319643548568-13.305782198227.9801898017-6.33881373431
52.24912331537-0.652505948340.8236726157692.239942084130.4486959984581.78178642576-0.1202022906560.5517454157820.537549225031-0.229355765480.01355310852860.1129314863920.02658461176570.02912426860310.1024247170850.3943883545430.0119351877753-0.06634563842820.5130460638040.1894754865380.468075691916-19.957550269839.9671858482-7.39267458828
63.743375423380.6049941760891.316737940572.196058666731.060457100410.797411366341-0.2795463428970.03010618202191.98297332238-0.14899014778-0.043208225859-0.304177989937-0.3084780380430.003170482827230.1759603684170.4349984498650.0298443711035-0.1234992986220.4173344277460.1375724702930.864862793364-15.990480027550.42851116030.511479079825
73.34496413047-0.1827893286340.7936434416691.453715585310.6954647926040.568699715532-0.528857394204-0.3740298348241.35606793740.393287043080.148964643096-0.263760092674-0.647831514988-0.04369619732270.3480772430960.5176886849550.0591959674831-0.09622039005820.458119610837-0.07453711692140.81929796556-11.363954140950.21171069717.8940468564
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 428 )
3X-RAY DIFFRACTION3chain 'A' and (resid 429 through 452 )
4X-RAY DIFFRACTION4chain 'A' and (resid 453 through 499 )
5X-RAY DIFFRACTION5chain 'A' and (resid 500 through 546 )
6X-RAY DIFFRACTION6chain 'A' and (resid 547 through 589 )
7X-RAY DIFFRACTION7chain 'A' and (resid 590 through 612 )

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