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Basic information

Entry
Database: PDB / ID: 8xgk
TitleOptimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Ihhibitors
ComponentsKelch-like ECH-associated protein 1
KeywordsPEPTIDE BINDING PROTEIN / chronic kidney disease (CKD) / Keap1 / Nrf2 / non-covalent inhibitor
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / centriolar satellite / cellular response to interleukin-4 / inclusion body / regulation of autophagy / actin filament / negative regulation of DNA-binding transcription factor activity ...regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / centriolar satellite / cellular response to interleukin-4 / inclusion body / regulation of autophagy / actin filament / negative regulation of DNA-binding transcription factor activity / disordered domain specific binding / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / cellular response to oxidative stress / Neddylation / midbody / ubiquitin-dependent protein catabolic process / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / protein ubiquitination / Ub-specific processing proteases / endoplasmic reticulum / 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
: / ACETATE ION / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.32 Å
AuthorsOtake, K. / Hara, Y. / Ubukata, M. / Inoue, M. / Nagahashi, N. / Motoda, D. / Ogawa, N. / Hantani, Y. / Hantani, R. / Adachi, T. ...Otake, K. / Hara, Y. / Ubukata, M. / Inoue, M. / Nagahashi, N. / Motoda, D. / Ogawa, N. / Hantani, Y. / Hantani, R. / Adachi, T. / Nomura, A. / Yamaguchi, K. / Maekawa, M. / Mamada, H. / Motomura, T. / Sato, M. / Harada, K.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: J.Med.Chem. / Year: 2024
Title: Optimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction Inhibitors.
Authors: Otake, K. / Hara, Y. / Ubukata, M. / Inoue, M. / Nagahashi, N. / Motoda, D. / Ogawa, N. / Hantani, Y. / Hantani, R. / Adachi, T. / Nomura, A. / Yamaguchi, K. / Maekawa, M. / Mamada, H. / ...Authors: Otake, K. / Hara, Y. / Ubukata, M. / Inoue, M. / Nagahashi, N. / Motoda, D. / Ogawa, N. / Hantani, Y. / Hantani, R. / Adachi, T. / Nomura, A. / Yamaguchi, K. / Maekawa, M. / Mamada, H. / Motomura, T. / Sato, M. / Harada, K.
History
DepositionDec 15, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0May 22, 2024Provider: repository / Type: Initial release

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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)35,92210
Polymers34,7301
Non-polymers1,1929
Water6,215345
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area190 Å2
ΔGint-16 kcal/mol
Surface area11910 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.251, 103.251, 55.186
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 / Kelch-like protein 19


Mass: 34730.027 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli BL21 (bacteria) / References: UniProt: Q14145
#2: Chemical ChemComp-A1LVB / (2~{R},3~{S})-3-[[(2~{S})-2-(4-chlorophenyl)-2-fluoranyl-ethanoyl]amino]-3-[3-(2-cyano-2-methyl-propoxy)-4-methyl-phenyl]-2-methyl-propanoic acid


Mass: 460.926 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C24H26ClFN2O4
#3: Chemical ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H3O2
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 345 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestN

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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: 2.45 Å3/Da / Density % sol: 49.69 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 5
Details: The purified Keap1 Kelch domain was concentrated to 6-10 mg/mL and crystallized with the solution containing 0.1 M Na acetate (pH 5.0) and 1.5 M di-ammonium sulfate, and 0-0.15 M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: Photon Factory / Beamline: BL-17A / Wavelength: 0.98 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Jun 2, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.98 Å / Relative weight: 1
ReflectionResolution: 1.32→89.42 Å / Num. obs: 76523 / % possible obs: 97.1 % / Redundancy: 20.8 % / Biso Wilson estimate: 12.23 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.017 / Rrim(I) all: 0.079 / Net I/σ(I): 4.4
Reflection shellResolution: 1.32→1.34 Å / Rmerge(I) obs: 0.805 / Num. unique obs: 3706

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.32→46.96 Å / SU ML: 0.0997 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 16.6831
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1686 3880 5.07 %
Rwork0.1624 72635 -
obs0.1627 76515 97.18 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 17.76 Å2
Refinement stepCycle: LAST / Resolution: 1.32→46.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2240 0 71 345 2656
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.01672502
X-RAY DIFFRACTIONf_angle_d1.96893435
X-RAY DIFFRACTIONf_chiral_restr0.2051354
X-RAY DIFFRACTIONf_plane_restr0.0157456
X-RAY DIFFRACTIONf_dihedral_angle_d7.3819375
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.32-1.340.17721280.21562573X-RAY DIFFRACTION95.31
1.34-1.350.20151300.2042533X-RAY DIFFRACTION94.8
1.35-1.370.21881420.22475X-RAY DIFFRACTION95.09
1.37-1.390.1771170.19372557X-RAY DIFFRACTION95.67
1.39-1.410.17721350.1832541X-RAY DIFFRACTION95.03
1.41-1.430.21651290.18472578X-RAY DIFFRACTION96.23
1.43-1.450.21061140.18312549X-RAY DIFFRACTION94.94
1.45-1.480.1631450.17882561X-RAY DIFFRACTION96.78
1.48-1.50.18111440.17572510X-RAY DIFFRACTION95.81
1.5-1.530.17171620.17322527X-RAY DIFFRACTION96.21
1.53-1.560.18641360.17812607X-RAY DIFFRACTION96.82
1.56-1.590.1661480.17012536X-RAY DIFFRACTION96.34
1.59-1.630.17511560.16562586X-RAY DIFFRACTION96.79
1.63-1.660.17231200.16242549X-RAY DIFFRACTION97.13
1.66-1.70.17141210.16832588X-RAY DIFFRACTION96.78
1.7-1.750.18171430.16012617X-RAY DIFFRACTION97.56
1.75-1.80.1621540.15432578X-RAY DIFFRACTION97.71
1.8-1.860.20141430.16022620X-RAY DIFFRACTION97.84
1.86-1.930.1551420.16052580X-RAY DIFFRACTION97.81
1.93-20.161410.1562628X-RAY DIFFRACTION98.19
2-2.10.14731570.14962619X-RAY DIFFRACTION98.2
2.1-2.210.13871230.14572647X-RAY DIFFRACTION98.02
2.21-2.340.15671170.15812655X-RAY DIFFRACTION99.04
2.34-2.530.17011260.16522657X-RAY DIFFRACTION98.69
2.53-2.780.14821400.17552670X-RAY DIFFRACTION99.19
2.78-3.180.17261670.16592636X-RAY DIFFRACTION99.47
3.18-40.17331540.14812698X-RAY DIFFRACTION99.62
4.01-46.960.16971460.15482760X-RAY DIFFRACTION99.79
Refinement TLS params.Method: refined / Origin x: 23.0634286712 Å / Origin y: 61.6860432648 Å / Origin z: 38.255616427 Å
111213212223313233
T0.0894908436828 Å20.00929886003095 Å2-0.0194702493091 Å2-0.080551434125 Å20.0060773768979 Å2--0.0951873810665 Å2
L0.689108130818 °2-0.207971944065 °2-0.155345155362 °2-1.27402809413 °20.0485314497571 °2--0.498788084111 °2
S-0.0111940404339 Å °-0.0117138849683 Å °-0.0207327482818 Å °0.0335056190751 Å °0.00734681253993 Å °0.116412904647 Å °0.0195506466003 Å °-0.0247226531807 Å °0.000786030678511 Å °
Refinement TLS groupSelection details: all

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