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- PDB-9ety: KEAP1 in complex with compound 25 -

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Basic information

Entry
Database: PDB / ID: 9ety
TitleKEAP1 in complex with compound 25
ComponentsKelch-like ECH-associated protein 1
KeywordsLIGASE / BTB / KEAP1
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / 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 ...regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / 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 / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / midbody / cellular response to oxidative stress / ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / regulation of autophagy / Ub-specific processing proteases / protein ubiquitination / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / nucleoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Kelch-like ECH-associated protein 1 / : / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif / Kelch repeat type 1 ...Kelch-like ECH-associated protein 1 / : / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif / 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
: / PHOSPHATE ION / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.87 Å
AuthorsRichardson, W. / Bullock, A.N. / Rothweiler, E.M. / Manning, C.E. / Sweeney, M.N. / Chalk, R. / Huber, K.V.M.
Funding support Switzerland, 1items
OrganizationGrant numberCountry
Innovative Medicines Initiative875510 Switzerland
CitationJournal: J.Med.Chem. / Year: 2024
Title: Covalent Inhibitors of KEAP1 with Exquisite Selectivity.
Authors: Fejes, I. / Markacz, P. / Tatai, J. / Rudas, M. / Dunkel, P. / Gyuris, M. / Nyerges, M. / Provost, N. / Duvivier, V. / Delerive, P. / Martiny, V. / Bristiel, A. / Vidal, B. / Richardson, W. ...Authors: Fejes, I. / Markacz, P. / Tatai, J. / Rudas, M. / Dunkel, P. / Gyuris, M. / Nyerges, M. / Provost, N. / Duvivier, V. / Delerive, P. / Martiny, V. / Bristiel, A. / Vidal, B. / Richardson, W. / Rothweiler, E.M. / Tranberg-Jensen, J. / Manning, C.E. / Sweeney, M.N. / Chalk, R. / Huber, K.V.M. / Bullock, A.N. / Herner, A. / Seedorf, K. / Vinson, C. / Weber, C. / Kotschy, A.
History
DepositionMar 27, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 11, 2024Provider: repository / Type: Initial release
Revision 1.1Dec 25, 2024Group: 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

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)43,7759
Polymers42,6752
Non-polymers1,1007
Water1,71195
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)38.991, 60.839, 165.517
Angle α, β, γ (deg.)90.00, 90.00, 90.00
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Kelch-like ECH-associated protein 1 / Cytosolic inhibitor of Nrf2 / INrf2 / Kelch-like protein 19


Mass: 21337.344 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Details: KEAP1 / Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Chemical ChemComp-A1H7T / 2-[[5-[(2~{R})-2,4-dimethyl-3-oxidanylidene-piperazin-1-yl]-2,3-dihydro-1,3-thiazol-4-yl]sulfonyl]benzenecarbonitrile


Mass: 378.469 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18N4O3S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-EDO / 1,2-ETHANEDIOL / ETHYLENE GLYCOL


Mass: 62.068 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C2H6O2
#4: Chemical ChemComp-PO4 / PHOSPHATE ION


Mass: 94.971 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: PO4
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 95 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationY

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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: 2.3 Å3/Da / Density % sol: 46.53 % / Description: Plates
Crystal growTemperature: 277.15 K / Method: vapor diffusion, sitting drop / pH: 8.5
Details: 20% PEG3350, 10% ethylene glycol, 0.1M bis-tris-propane pH 8.5, 0.02M sodium/potassium phosphate

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I03 / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Feb 13, 2022
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.87→57.2 Å / Num. obs: 33449 / % possible obs: 99.79 % / Redundancy: 13.2 % / CC1/2: 0.998 / Net I/σ(I): 12.5
Reflection shellResolution: 1.87→1.9 Å / Num. unique obs: 1617 / CC1/2: 0.26

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Processing

Software
NameVersionClassification
REFMAC5.8.0238refinement
xia2data scaling
xia2data reduction
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.87→57.17 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.949 / SU B: 5.996 / SU ML: 0.157 / Cross valid method: THROUGHOUT / ESU R: 0.153 / ESU R Free: 0.147 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.25521 1670 5.1 %RANDOM
Rwork0.21064 ---
obs0.21288 31352 98.47 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 43.713 Å2
Baniso -1Baniso -2Baniso -3
1-0.88 Å20 Å20 Å2
2--1.74 Å20 Å2
3----2.62 Å2
Refinement stepCycle: 1 / Resolution: 1.87→57.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2674 0 71 95 2840
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0132820
X-RAY DIFFRACTIONr_bond_other_d0.0010.0172536
X-RAY DIFFRACTIONr_angle_refined_deg1.4851.6353808
X-RAY DIFFRACTIONr_angle_other_deg1.3711.5665867
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.3335346
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.14522.416149
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.00515468
X-RAY DIFFRACTIONr_dihedral_angle_4_deg16.7671513
X-RAY DIFFRACTIONr_chiral_restr0.0750.2364
X-RAY DIFFRACTIONr_gen_planes_refined0.0070.023166
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02589
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it3.5264.5391378
X-RAY DIFFRACTIONr_mcbond_other3.5274.5361377
X-RAY DIFFRACTIONr_mcangle_it5.1586.7831720
X-RAY DIFFRACTIONr_mcangle_other5.1576.7871721
X-RAY DIFFRACTIONr_scbond_it4.5595.0691442
X-RAY DIFFRACTIONr_scbond_other4.5435.0561439
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other6.9327.4032081
X-RAY DIFFRACTIONr_long_range_B_refined9.45554.1823102
X-RAY DIFFRACTIONr_long_range_B_other9.44154.1523090
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.87→1.919 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.447 98 -
Rwork0.439 1943 -
obs--83.61 %

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