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- PDB-8ixs: Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1/Nr... -

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Basic information

Entry
Database: PDB / ID: 8ixs
TitleMethyl and Fluorine Effects in Novel Orally Bioavailable Keap1/Nrf2 PPI Inhibitor for Treatment of Chronic Kidney Disease
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 / inclusion body / cellular response to interleukin-4 / 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 / inclusion body / cellular response to interleukin-4 / regulation of autophagy / actin filament / negative regulation of DNA-binding transcription factor activity / KEAP1-NFE2L2 pathway / disordered domain specific binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / 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
Chem-T6I / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.48 Å
AuthorsNomura, A. / Yamaguchi, K. / Adachi, T.
Funding support1items
OrganizationGrant numberCountry
Not funded
CitationJournal: Acs Med.Chem.Lett. / Year: 2023
Title: Methyl and Fluorine Effects in Novel Orally Bioavailable Keap1-Nrf2 PPI Inhibitor.
Authors: Otake, K. / Ubukata, M. / Nagahashi, N. / Ogawa, N. / Hantani, Y. / Hantani, R. / Adachi, T. / Nomura, A. / Yamaguchi, K. / Maekawa, M. / Mamada, H. / Motomura, T. / Sato, M. / Harada, K.
History
DepositionApr 3, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 14, 2023Provider: 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)35,6908
Polymers34,7301
Non-polymers9607
Water7,674426
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area200 Å2
ΔGint-17 kcal/mol
Surface area12190 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.589, 103.589, 55.190
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 (E. coli) / References: UniProt: Q14145
#2: Chemical ChemComp-T6I / (2R,3S)-3-[[(2S)-2-fluoranyl-2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanoyl]amino]-2-methyl-3-(4-methylphenyl)propanoic acid


Mass: 383.456 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H26FNO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: SO4
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 426 / 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: 2.46 Å3/Da / Density % sol: 50.03 %
Crystal growTemperature: 278 K / Method: vapor diffusion / pH: 7.5
Details: 6-10mg/mL and crystallized with the solution with 0.1M Na acetate (pH5.0) and 1.5M di-ammonium sulfate or the solution with 0.1M Na acetate (pH5.0), 1.5M di-ammonium, and 0.1-0.15M NaCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: SPring-8 / Beamline: BL41XU / Wavelength: 1 Å
DetectorType: MARMOSAIC 225 mm CCD / Detector: CCD / Date: Jul 15, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.48→89.71 Å / Num. obs: 56260 / % possible obs: 99.5 % / Redundancy: 29.2 % / Rmerge(I) obs: 0.092 / Rpim(I) all: 0.017 / Rrim(I) all: 0.093 / Net I/σ(I): 3.9
Reflection shellResolution: 1.48→1.52 Å / Redundancy: 19.8 % / Rmerge(I) obs: 0.913 / Mean I/σ(I) obs: 3.9 / Num. unique obs: 3884 / CC1/2: 0.903 / Rpim(I) all: 0.193 / Rrim(I) all: 0.935 / % possible all: 93.7

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.48→89.71 Å / SU ML: 0.1522 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 17.5353
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1905 2840 5.05 %
Rwork0.1641 53380 -
obs0.1654 56220 99.51 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 21.83 Å2
Refinement stepCycle: LAST / Resolution: 1.48→89.71 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2251 0 58 426 2735
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00222411
X-RAY DIFFRACTIONf_angle_d0.59183297
X-RAY DIFFRACTIONf_chiral_restr0.0757343
X-RAY DIFFRACTIONf_plane_restr0.0049433
X-RAY DIFFRACTIONf_dihedral_angle_d10.5895859
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.48-1.50.29391140.25062458X-RAY DIFFRACTION90.69
1.5-1.530.2241480.2172642X-RAY DIFFRACTION100
1.53-1.560.18391650.19252639X-RAY DIFFRACTION99.96
1.56-1.590.21391440.17312667X-RAY DIFFRACTION99.93
1.59-1.630.20121380.17032679X-RAY DIFFRACTION100
1.63-1.670.1871540.15982633X-RAY DIFFRACTION99.86
1.67-1.710.19091330.16022680X-RAY DIFFRACTION99.93
1.71-1.750.1851310.15952679X-RAY DIFFRACTION100
1.75-1.80.17111330.16052684X-RAY DIFFRACTION100
1.8-1.860.2061530.16782658X-RAY DIFFRACTION100
1.86-1.930.19591390.17282679X-RAY DIFFRACTION100
1.93-2.010.17841350.15442670X-RAY DIFFRACTION100
2.01-2.10.17811380.15582688X-RAY DIFFRACTION100
2.1-2.210.16761570.15462685X-RAY DIFFRACTION100
2.21-2.350.18741470.15852682X-RAY DIFFRACTION100
2.35-2.530.20651420.16932674X-RAY DIFFRACTION100
2.53-2.780.1981530.17172675X-RAY DIFFRACTION100
2.78-3.190.18811450.16592702X-RAY DIFFRACTION100
3.19-4.010.17681390.15292713X-RAY DIFFRACTION100
4.01-89.710.19781320.16092793X-RAY DIFFRACTION99.97
Refinement TLS params.Method: refined / Origin x: 23.045 Å / Origin y: 61.625 Å / Origin z: 38.401 Å
111213212223313233
T-0.0716383261818 Å20.032357442061 Å2-0.0911272665609 Å2--0.0448006936634 Å20.0182858338164 Å2---0.178476922031 Å2
L2.60577166746 °2-0.094773468482 °2-0.719623477492 °2-4.63636237175 °2-0.00854363292288 °2--1.97571799743 °2
S-0.016797422812 Å °0.023058618275 Å °0.0109915058043 Å °0.101897618434 Å °0.0327367073543 Å °0.402962146454 Å °0.0343304379133 Å °-0.138007683446 Å °0.019568940732 Å °
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1( CHAIN A AND ( RESID 321:613 OR RESID 701:701 ) )A321 - 613
2X-RAY DIFFRACTION1( CHAIN A AND ( RESID 321:613 OR RESID 701:701 ) )A701

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