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- PDB-7of8: Keap1 kelch domain bound to a small molecule fragment -

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Basic information

Entry
Database: PDB / ID: 7of8
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


cellular response to carbohydrate stimulus / KEAP1-NFE2L2 pathway / regulation of epidermal cell differentiation / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / centriolar satellite / ubiquitin-like ligase-substrate adaptor activity ...cellular response to carbohydrate stimulus / KEAP1-NFE2L2 pathway / regulation of epidermal cell differentiation / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / centriolar satellite / ubiquitin-like ligase-substrate adaptor activity / cellular response to interleukin-4 / inclusion body / 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-VCQ / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.78 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)33,5832
Polymers33,3621
Non-polymers2201
Water1,74797
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11980 Å2
Unit cell
Length a, b, c (Å)104.320, 104.320, 55.986
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-VCQ / (2~{S})-2-cyclopentyl-2-oxidanyl-2-phenyl-ethanoic acid


Mass: 220.264 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C13H16O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 97 / 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: 2.57 Å3/Da / Density % sol: 52.2 %
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 25, 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: 1.779→38.16 Å / Num. obs: 33483 / % possible obs: 99.71 % / Redundancy: 13.3 % / Biso Wilson estimate: 26.76 Å2 / CC1/2: 0.998 / CC star: 0.999 / Rmerge(I) obs: 0.1237 / Rpim(I) all: 0.03472 / Rrim(I) all: 0.1286 / Net I/σ(I): 11.12
Reflection shellResolution: 1.779→1.843 Å / Redundancy: 9.8 % / Rmerge(I) obs: 0.8104 / Mean I/σ(I) obs: 2.12 / Num. unique obs: 3311 / CC1/2: 0.631 / CC star: 0.88 / Rpim(I) all: 0.271 / Rrim(I) all: 0.8558 / % possible all: 99.31

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Processing

Software
NameVersionClassification
DIALS1.9.3data reduction
Aimless0.7.1data scaling
PHASER1.13_2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 1.78→38.16 Å / SU ML: 0.2314 / Cross valid method: FREE R-VALUE / σ(F): 1.51 / Phase error: 25.2276 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.2238 1628 4.87 %Random
Rwork0.1879 31784 --
obs0.1896 33412 99.72 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 44.67 Å2
Refinement stepCycle: LAST / Resolution: 1.78→38.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2213 0 16 97 2326
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01472289
X-RAY DIFFRACTIONf_angle_d1.23733118
X-RAY DIFFRACTIONf_chiral_restr0.0795329
X-RAY DIFFRACTIONf_plane_restr0.0088411
X-RAY DIFFRACTIONf_dihedral_angle_d12.28231332
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.78-1.830.33731490.31222630X-RAY DIFFRACTION99.18
1.83-1.890.30361520.29792620X-RAY DIFFRACTION100
1.89-1.960.47521100.3932600X-RAY DIFFRACTION98.47
1.96-2.040.25141560.22552623X-RAY DIFFRACTION100
2.04-2.130.2591400.21992650X-RAY DIFFRACTION100
2.13-2.240.26921350.22635X-RAY DIFFRACTION99.96
2.24-2.380.30321550.25092600X-RAY DIFFRACTION99.07
2.38-2.570.2281250.19012660X-RAY DIFFRACTION100
2.57-2.820.24261440.17982662X-RAY DIFFRACTION100
2.82-3.230.23961090.1832670X-RAY DIFFRACTION100
3.23-4.070.20811150.16632693X-RAY DIFFRACTION100
4.07-38.160.14111380.13542741X-RAY DIFFRACTION99.93
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)
17.51995634149-3.505121163832.052512252883.26617231628-2.768498156045.52011874788-0.106746194616-0.693306380158-0.788931761660.04618722501310.07157861312980.04860780793890.27571549648-0.196304792544-0.002553126719360.229499931415-0.02372305569550.06281433985450.2665759416240.08941880613170.364278103275.21202349596-49.669421585410.7349998174
24.461066291262.125269139390.1904421125314.08271477502-1.568835523493.147108412760.0761252373212-0.379948401938-0.1521054715070.31392124623-0.02993005774860.269682947249-0.2003382237810.0811618894764-0.005709408430370.2204651302280.02343264647270.0342306609750.316150322077-0.03484831146830.2811501663991.72805105069-38.91392634519.92875204366
32.37073572511-1.38368021795-0.6099826163935.61198030842-2.87593569692.31052197227-0.0596450243757-0.289040954245-0.1937954245110.1139534476820.06804460192990.60263294771-0.199601110217-0.4527013082350.1335765959860.161328134386-0.01379135697270.03546002172610.3677480874450.004185767975390.378615977697-3.79009692063-38.98701378378.60971481889
46.38616613020.384138044805-0.2025210704193.00803633691-0.5536561211461.502187630070.002926553994850.01671631913820.4515751546040.002311007384690.0370624553140.20258017963-0.302953601478-0.0357402827391-0.06655853579520.2345274610750.0139874904307-0.0283700533880.221086481197-0.02917964131280.2638801235486.6387456793-28.350201690.206289389867
55.1252849982-0.4357342670121.91588819946.832030854995.673634222528.7405385476-0.1074979003330.6620175287610.469878641021-0.6260424250270.09339523905170.0591796343946-0.3732546939220.137225033145-0.01378529436920.2616926583460.0006947991943780.0009272497257440.3045101896430.1034442626230.18009353497813.9191337345-27.9320611237-8.92499416896
65.61513583171-0.223740735335-1.248419267225.43397054077-1.814215003411.950618435680.008645617718310.525950033403-0.25357077305-0.3224915667790.0638931193943-0.2427239938610.02863897130130.153971143503-0.0798289393020.202411679528-0.006272557501110.03578776331820.287095904189-0.08380828354710.17798649030520.6181138467-40.5935736557-7.41790961993
76.344540574181.47048928094-1.043112163193.567583118161.935082626077.8029330264-0.125398745230.00561938658333-0.8470918534670.149096806023-0.00561227933335-0.1605047155950.4630504174370.2113100138180.03624623753410.195601177540.0365378229943-0.007797943975910.16811352547-0.01696980473390.29334702553317.1936817589-48.8943265091.59885078511
86.516529715530.355748210528-1.151440894782.92846523755-0.5911672593891.18391215316-0.202712260061-0.207022986856-1.159155756310.1090987105940.03311946127380.00522736343810.2119027550110.105787036060.06838616653120.235907097090.00551894901415-0.00223530683180.2492395295260.002049720323870.37308605948112.9812334075-51.57517041753.94224127596
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 325 through 354 )
2X-RAY DIFFRACTION2chain 'A' and (resid 355 through 377 )
3X-RAY DIFFRACTION3chain 'A' and (resid 378 through 405 )
4X-RAY DIFFRACTION4chain 'A' and (resid 406 through 475 )
5X-RAY DIFFRACTION5chain 'A' and (resid 476 through 499 )
6X-RAY DIFFRACTION6chain 'A' and (resid 500 through 546 )
7X-RAY DIFFRACTION7chain 'A' and (resid 547 through 569 )
8X-RAY DIFFRACTION8chain 'A' and (resid 570 through 612 )

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