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

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Basic information

Entry
Database: PDB / ID: 7ofb
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
Chem-VCN / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.4 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)34,2069
Polymers33,3621
Non-polymers8448
Water543
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1400 Å2
ΔGint2 kcal/mol
Surface area12070 Å2
Unit cell
Length a, b, c (Å)103.364, 103.364, 55.485
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.: 1 / Source method: obtained synthetically / Formula: SO4
#3: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#4: Chemical ChemComp-VCN / ~{N},~{N}-diethyl-9-oxidanylidene-fluorene-4-carboxamide


Mass: 279.333 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C18H17NO2 / Feature type: SUBJECT OF INVESTIGATION
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 3 / 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: 2.5 Å3/Da / Density % sol: 50.9 %
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: 1.0723 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 25, 2018 / Details: Toroidal mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.4→47.16 Å / Num. obs: 13361 / % possible obs: 99.87 % / Redundancy: 6.7 % / Biso Wilson estimate: 36.59 Å2 / CC1/2: 0.997 / CC star: 0.999 / Rmerge(I) obs: 0.07886 / Rpim(I) all: 0.03344 / Rrim(I) all: 0.08581 / Net I/σ(I): 14.55
Reflection shellResolution: 2.4→2.486 Å / Redundancy: 6.8 % / Rmerge(I) obs: 0.3351 / Mean I/σ(I) obs: 4.27 / Num. unique obs: 1308 / CC1/2: 0.975 / CC star: 0.994 / Rpim(I) all: 0.1387 / Rrim(I) all: 0.3632 / % possible all: 99.69

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Processing

Software
NameVersionClassification
XDSv Jan 26, 2018data reduction
XDSv Jan 26, 2018data scaling
PHASER1.13_2998phasing
PHENIX1.13_2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 2.4→47.16 Å / SU ML: 0.2442 / Cross valid method: FREE R-VALUE / σ(F): 1.38 / Phase error: 28.0972 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.2251 666 4.99 %Random
Rwork0.1909 12686 --
obs0.1927 13352 99.89 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 50.97 Å2
Refinement stepCycle: LAST / Resolution: 2.4→47.16 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 50 3 2272
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00392319
X-RAY DIFFRACTIONf_angle_d0.73713152
X-RAY DIFFRACTIONf_chiral_restr0.0499328
X-RAY DIFFRACTIONf_plane_restr0.004414
X-RAY DIFFRACTIONf_dihedral_angle_d12.52281336
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.4-2.590.28551300.24232495X-RAY DIFFRACTION99.89
2.59-2.850.31821350.23672530X-RAY DIFFRACTION99.93
2.85-3.260.27151330.23392534X-RAY DIFFRACTION99.89
3.26-4.10.20931350.19052528X-RAY DIFFRACTION99.92
4.1-47.160.17311330.14832599X-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)
10.315679916214-0.0213163922653-0.06903805298220.00649565178898-0.001176762174080.02231340610790.10337186802-0.00795347748657-0.447271447202-0.286761757336-0.3239248301250.2951782617980.370786454117-0.445571688038-0.008302879935580.390559979138-0.00695308595666-0.06726673488060.393233723925-0.06731943419810.491948712592-42.3000395757-21.8744014883-7.28491597587
20.2715509752390.08933011072430.1224672222110.6889554331250.3303756997260.1189926139080.08631733628570.0417231877219-0.408353971894-0.151963690902-0.109101750490.175532514177-0.04537906337640.0074081068607-1.73394231165E-50.3770631235970.0733608654042-0.03069436192320.339723825616-0.05478911287290.409188946864-39.989565051-17.6622120813-12.1905037168
30.09582895289470.1452579404780.1281512812260.241228397470.2172263900460.188528715276-0.001194755552420.0774477525732-0.417053821262-0.0003846998484560.08483862725180.0107332428079-0.1902914988790.01619849553580.0001289306249460.367963950650.0724942391613-0.02493832461870.342417955944-0.02526346174590.392869443871-31.286665706-22.5061158199-8.80181748457
40.4184523649440.152095806750.4425091209550.6439787195120.5733523201660.77023447163-0.0386646558590.006045767807490.06712524887660.1062482473950.0476867501807-0.2391696457230.03975818992690.1843259688171.01863824968E-50.3357455095340.02184941163360.02768039841030.3450910513220.02893503289490.311050997793-27.1918198245-8.31962137609-0.281896474815
50.847704098716-0.477126922176-0.2518202000680.5405502857980.2185639558140.319167573448-0.041334038892-0.1300894562820.01100187815310.1417987547230.03328084471350.0671154874367-0.01974768340970.0136027709894-4.02046753747E-50.4010061267880.004740672256270.03033821467010.3585454822820.03243898594670.329658090787-39.7364400226-2.23563238357.95635024142
60.2966835911680.0935290893110.03251699358420.5152868852620.5398451174320.5274927833670.05250323272-0.0821723639128-0.250477021403-0.2372558190680.04266679667050.662866871141-0.00387590971255-0.364736842708-1.69039177075E-50.3588511772850.02021235280390.02074496436390.3953240467670.02693552157070.432127889059-50.3847569208-9.38819276033-1.5445136635
70.2244975828960.02160761246940.1066163288030.8118169454490.4530649514110.791852142046-0.01388110010950.061758738472-0.452829766243-0.0293047873366-0.1044230484530.6312050662830.144438761999-0.195890301284-2.53063093125E-50.3375842090620.0002307307051230.0006967341205640.3227318379640.008974015915850.525093980831-50.4507512714-14.3918728786-4.45173674085
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 405 )
4X-RAY DIFFRACTION4chain 'A' and (resid 406 through 475 )
5X-RAY DIFFRACTION5chain 'A' and (resid 476 through 546 )
6X-RAY DIFFRACTION6chain 'A' and (resid 547 through 569 )
7X-RAY DIFFRACTION7chain 'A' and (resid 570 through 613 )

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