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- PDB-9du7: KEAP1 BTB domain in complex with the covalent activator VVD-065 -

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Basic information

Entry
Database: PDB / ID: 9du7
TitleKEAP1 BTB domain in complex with the covalent activator VVD-065
ComponentsKelch-like ECH-associated protein 1
KeywordsPROTEIN BINDING / KEAP1 / E3 ligase
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
: / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.867 Å
AuthorsBernard, S.M.
Funding support United States, 1items
OrganizationGrant numberCountry
Other private United States
CitationJournal: Biorxiv / Year: 2024
Title: Suppression of NRF2-dependent cancer growth by a covalent allosteric molecular glue
Authors: Roy, N. / Wyseure, T. / Lo, I.C. / Metzger, J. / Eissler, C.L. / Bernard, S.M. / Bok, I. / Snead, A.N. / Parker, A. / Green, J.C. / Inloes, J. / Jacinto, S.R. / Kuenzi, B. / Horning, B.D. / ...Authors: Roy, N. / Wyseure, T. / Lo, I.C. / Metzger, J. / Eissler, C.L. / Bernard, S.M. / Bok, I. / Snead, A.N. / Parker, A. / Green, J.C. / Inloes, J. / Jacinto, S.R. / Kuenzi, B. / Horning, B.D. / Ibrahim, N. / Grabow, S. / Panda, H. / Bhatt, D.P. / Saeidi, S. / Zolkind, P. / Rush, Z. / Negri, K. / Williams, H.N. / Walton, E. / Pastuszka, M.K. / Sigler, J.J. / Tran, E. / Hee, K. / McLaughlin, J. / Ambrus-Aikelin, G. / Pollock, J. / Abraham, R.T. / Kinsella, T.M. / Simon, G.M. / Major, M.B. / Weinstein, D.S. / Patricelli, M.P.
History
DepositionOct 2, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Oct 23, 2024Provider: repository / Type: Initial release

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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
B: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)31,2834
Polymers30,5872
Non-polymers6962
Water2,090116
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area5030 Å2
ΔGint-34 kcal/mol
Surface area13040 Å2
MethodPISA
Unit cell
Length a, b, c (Å)72.737, 72.737, 64.209
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number78
Space group name H-MP43

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Components

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


Mass: 15293.651 Da / Num. of mol.: 2
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Chemical ChemComp-A1BCT / 1-{(3S)-3-[3-(4-amino-1,3,5-triazin-2-yl)-5-chlorophenyl]morpholin-4-yl}propan-1-one


Mass: 347.799 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H18ClN5O2 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 116 / 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: 2.78 Å3/Da / Density % sol: 55.7 %
Crystal growTemperature: 293.15 K / Method: vapor diffusion, sitting drop / pH: 9.2 / Details: 24% PEG 3350, 100 mM CHES pH 9.2

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ALS / Beamline: 5.0.2 / Wavelength: 1.00003 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: May 28, 2021
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.00003 Å / Relative weight: 1
ReflectionResolution: 1.867→48.183 Å / Num. obs: 27387 / % possible obs: 98.21 % / Redundancy: 6.9 % / Biso Wilson estimate: 42.64 Å2 / CC1/2: 0.998 / CC star: 0.999 / Rmerge(I) obs: 0.0625 / Rpim(I) all: 0.02625 / Rrim(I) all: 0.06795 / Net I/σ(I): 15.21
Reflection shellResolution: 1.87→1.937 Å / Num. unique obs: 2674 / CC1/2: 0.525

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Processing

Software
NameVersionClassification
REFMAC5.8.0405refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.867→48.183 Å / Cor.coef. Fo:Fc: 0.966 / Cor.coef. Fo:Fc free: 0.957 / SU B: 3.601 / SU ML: 0.103 / Cross valid method: FREE R-VALUE / ESU R: 0.128 / ESU R Free: 0.127
Details: Hydrogens have been added in their riding positions
RfactorNum. reflection% reflection
Rfree0.2314 1336 4.878 %
Rwork0.1915 26051 -
all0.194 --
obs-27387 98.144 %
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK BULK SOLVENT
Displacement parametersBiso mean: 44.499 Å2
Baniso -1Baniso -2Baniso -3
1--0.466 Å20 Å20 Å2
2---0.466 Å2-0 Å2
3---0.933 Å2
Refinement stepCycle: LAST / Resolution: 1.867→48.183 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms1974 0 48 116 2138
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0122060
X-RAY DIFFRACTIONr_bond_other_d0.0010.0161964
X-RAY DIFFRACTIONr_angle_refined_deg1.5891.6752779
X-RAY DIFFRACTIONr_angle_other_deg0.5321.5914515
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.9185251
X-RAY DIFFRACTIONr_dihedral_angle_2_deg5.45858
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.2110363
X-RAY DIFFRACTIONr_dihedral_angle_6_deg16.1151088
X-RAY DIFFRACTIONr_chiral_restr0.0790.2314
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.022358
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02464
X-RAY DIFFRACTIONr_nbd_refined0.2180.2432
X-RAY DIFFRACTIONr_symmetry_nbd_other0.1980.21744
X-RAY DIFFRACTIONr_nbtor_refined0.1880.21042
X-RAY DIFFRACTIONr_symmetry_nbtor_other0.0810.21107
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.1510.2112
X-RAY DIFFRACTIONr_symmetry_nbd_refined0.1240.27
X-RAY DIFFRACTIONr_nbd_other0.1980.234
X-RAY DIFFRACTIONr_symmetry_xyhbond_nbd_refined0.1580.23
X-RAY DIFFRACTIONr_mcbond_it4.1584.3441013
X-RAY DIFFRACTIONr_mcbond_other4.1584.3441013
X-RAY DIFFRACTIONr_mcangle_it5.4647.7711263
X-RAY DIFFRACTIONr_mcangle_other5.4617.7711263
X-RAY DIFFRACTIONr_scbond_it5.4975.0151047
X-RAY DIFFRACTIONr_scbond_other5.4955.0161048
X-RAY DIFFRACTIONr_scangle_it7.9578.9521516
X-RAY DIFFRACTIONr_scangle_other7.9548.9531517
X-RAY DIFFRACTIONr_lrange_it9.48245.8092445
X-RAY DIFFRACTIONr_lrange_other9.43745.5912417
LS refinement shell

Refine-ID: X-RAY DIFFRACTION / Total num. of bins used: 20

Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRfactor allNum. reflection allFsc freeFsc work% reflection obs (%)WRfactor Rwork
1.867-1.9160.328910.36318690.36220390.920.92596.12550.355
1.916-1.9680.352850.30718530.30919890.9180.94697.43590.287
1.968-2.0250.274850.26818110.26819480.9620.95797.33060.24
2.025-2.0870.323680.24317760.24618880.940.96397.66950.212
2.087-2.1550.3131020.22216910.22718380.9410.96997.55170.196
2.155-2.2310.208980.21216260.21217620.9720.97397.84340.188
2.231-2.3150.28810.20815810.21216950.9540.97398.05310.189
2.315-2.4090.322850.21315520.21916660.9290.97298.25930.197
2.409-2.5160.277680.19314900.19715820.9580.97898.48290.18
2.516-2.6390.25850.19614030.19915070.9630.97798.73920.188
2.639-2.7810.235670.19413720.19714660.9640.97898.15820.192
2.781-2.9490.213540.17912900.18113630.9680.98198.6060.183
2.949-3.1520.243620.19911880.20112590.9710.97899.28510.209
3.152-3.4030.264610.211200.20311980.9550.97698.5810.214
3.403-3.7260.25600.20410420.20611080.9710.97999.45850.225
3.726-4.1630.191470.1649550.16510090.9770.98499.30620.194
4.163-4.8010.195520.1428270.1458850.9820.98999.3220.181
4.801-5.8650.201430.1717140.1737610.9790.98699.47440.207
5.865-8.2330.212300.1745640.1765950.9810.98499.83190.216
8.233-48.1830.128120.23270.1973430.9930.97898.83380.246

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