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Basic information

Entry
Database: PDB / ID: 8xgv
TitleOptimization Efforts for Identification of Novel Highly Potent Keap1-Nrf2 Protein-Protein Interaction (PPI) Inhibitors
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 / 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 ...regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / 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 / 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 / Neddylation / cellular response to oxidative stress / midbody / ubiquitin-dependent protein catabolic process / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / Ub-specific processing proteases / protein ubiquitination / 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: 1.42 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 support Japan, 1items
OrganizationGrant numberCountry
Not funded Japan
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)35,7348
Polymers34,7301
Non-polymers1,0047
Water7,314406
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)103.581, 103.581, 55.469
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-A1LVC / (2~{R},3~{S})-3-[[(2~{S})-2-[4-[(3-ethoxypyridin-2-yl)methyl]phenyl]-2-fluoranyl-ethanoyl]amino]-2-methyl-3-(4-methylphenyl)propanoic acid


Mass: 464.529 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H29FN2O4
#3: Chemical ChemComp-ACT / ACETATE ION


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


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


Mass: 18.015 Da / Num. of mol.: 406 / 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: 2.47 Å3/Da / Density % sol: 50.27 %
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: 1.41→55.47 Å / Num. obs: 64842 / % possible obs: 99.1 % / Redundancy: 20.3 % / Biso Wilson estimate: 15.18 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.017 / Rrim(I) all: 0.079 / Net I/σ(I): 27.5
Reflection shellResolution: 1.41→1.43 Å / Num. unique obs: 3197 / CC1/2: 0.938

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.42→47.18 Å / SU ML: 0.1075 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 16.4174
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1689 3217 5.08 %
Rwork0.1671 60136 -
obs0.1672 63353 98.96 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.02 Å2
Refinement stepCycle: LAST / Resolution: 1.42→47.18 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2251 0 63 406 2720
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00922436
X-RAY DIFFRACTIONf_angle_d1.25793334
X-RAY DIFFRACTIONf_chiral_restr0.0957346
X-RAY DIFFRACTIONf_plane_restr0.0121442
X-RAY DIFFRACTIONf_dihedral_angle_d8.7232360
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.42-1.440.20511270.19342580X-RAY DIFFRACTION98.33
1.44-1.460.18381370.19012571X-RAY DIFFRACTION97.8
1.46-1.490.22731350.18762589X-RAY DIFFRACTION98.13
1.49-1.510.18511370.17662572X-RAY DIFFRACTION98.76
1.51-1.540.17921900.17262546X-RAY DIFFRACTION97.47
1.54-1.570.1971470.18342587X-RAY DIFFRACTION99.2
1.57-1.60.15421180.18262606X-RAY DIFFRACTION98.73
1.6-1.640.18091360.16962577X-RAY DIFFRACTION98.23
1.64-1.680.15511380.16592631X-RAY DIFFRACTION98.93
1.68-1.720.1631400.1652596X-RAY DIFFRACTION99.56
1.72-1.760.15831520.16052595X-RAY DIFFRACTION98.88
1.76-1.820.17381200.15892637X-RAY DIFFRACTION99.07
1.82-1.870.17811190.1692644X-RAY DIFFRACTION99.25
1.87-1.940.19191410.20932558X-RAY DIFFRACTION97.61
1.94-2.020.15051340.1582630X-RAY DIFFRACTION99.64
2.02-2.110.14251360.15322643X-RAY DIFFRACTION99.18
2.11-2.220.15241420.15172617X-RAY DIFFRACTION99.42
2.22-2.360.16431850.19162565X-RAY DIFFRACTION98.35
2.36-2.540.17961410.1722647X-RAY DIFFRACTION99.86
2.54-2.80.17491180.17322685X-RAY DIFFRACTION99.93
2.8-3.20.17891520.16932636X-RAY DIFFRACTION99.96
3.21-4.040.16131320.15172677X-RAY DIFFRACTION99.96
4.04-47.180.16581400.15872747X-RAY DIFFRACTION99.93
Refinement TLS params.Method: refined / Origin x: 23.2531157333 Å / Origin y: 61.68946399 Å / Origin z: 38.1455009661 Å
111213212223313233
T0.107889620586 Å20.0156302711022 Å2-0.0245715669731 Å2-0.106819675148 Å20.00807763947919 Å2--0.0941641755795 Å2
L0.842040506335 °2-0.248483537574 °2-0.226598048066 °2-1.49576484053 °20.137364943232 °2--0.645694188054 °2
S-0.0110939357582 Å °-0.0262993138472 Å °-0.0271553151803 Å °0.0540075033919 Å °0.0098313202421 Å °0.0956468679818 Å °0.0219939568406 Å °-0.0147296985063 Å °-0.0027485342524 Å °
Refinement TLS groupSelection details: all

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