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

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Basic information

Entry
Database: PDB / ID: 8ivg
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
2,3-DIHYDROXY-1,4-DITHIOBUTANE / Chem-SGO / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.8 Å
AuthorsOtake, K. / Ubukata, M. / Nagahashi, N. / Ogawa, N. / Hantani, Y. / Hantani, R. / Adachi, T. / Nomura, A. / Yamaguchi, K. / Maekawa, M. ...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.
Funding support Japan, 1items
OrganizationGrant numberCountry
Not funded Japan
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
DepositionMar 27, 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)36,10012
Polymers34,7301
Non-polymers1,37011
Water4,702261
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area210 Å2
ΔGint-18 kcal/mol
Surface area12270 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.149, 103.149, 55.004
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 / Plasmid: pET28b / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Chemical ChemComp-SGO / (3S)-3-(4-methylphenyl)-3-[2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanoylamino]propanoic acid


Mass: 351.439 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C22H25NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL / Dithiothreitol


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#4: Chemical
ChemComp-SO4 / SULFATE ION / Sulfate


Mass: 96.063 Da / Num. of mol.: 9 / Source method: obtained synthetically / Formula: SO4
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 261 / 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: 2.43 Å3/Da / Density % sol: 49.43 %
Crystal growTemperature: 278 K / Method: vapor diffusion / pH: 7.5
Details: 6-10 mg/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: SOLEIL / Beamline: PROXIMA 1 / Wavelength: 0.9786 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Dec 25, 2013
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9786 Å / Relative weight: 1
ReflectionResolution: 1.8→46.84 Å / Num. obs: 30486 / % possible obs: 98.1 % / Redundancy: 4.7 % / Biso Wilson estimate: 21.92 Å2 / Rmerge(I) obs: 0.047 / Net I/σ(I): 12.1
Reflection shellResolution: 1.8→1.85 Å / Rmerge(I) obs: 0.31 / Mean I/σ(I) obs: 2.5 / Num. unique obs: 2053

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
SCALAdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.8→46.84 Å / SU ML: 0.159 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 19.283
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1856 1548 5.08 %
Rwork0.1568 28926 -
obs0.1583 30474 98.06 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 32.17 Å2
Refinement stepCycle: LAST / Resolution: 1.8→46.84 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2251 0 79 261 2591
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00222377
X-RAY DIFFRACTIONf_angle_d0.65293240
X-RAY DIFFRACTIONf_chiral_restr0.0433337
X-RAY DIFFRACTIONf_plane_restr0.0045419
X-RAY DIFFRACTIONf_dihedral_angle_d16.0111822
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.8-1.860.28851300.23712421X-RAY DIFFRACTION90.94
1.86-1.920.23671390.21522526X-RAY DIFFRACTION95.21
1.92-20.20161310.1752616X-RAY DIFFRACTION97.93
2-2.090.19061590.1572634X-RAY DIFFRACTION98.9
2.09-2.20.18751480.14272637X-RAY DIFFRACTION99.11
2.2-2.340.17891360.15292653X-RAY DIFFRACTION99.43
2.34-2.520.20751250.16542672X-RAY DIFFRACTION99.54
2.52-2.780.20811560.17062668X-RAY DIFFRACTION99.61
2.78-3.180.18771420.16782668X-RAY DIFFRACTION99.72
3.18-40.18271500.13612699X-RAY DIFFRACTION99.86
4-46.840.14331320.14292732X-RAY DIFFRACTION98.35
Refinement TLS params.Method: refined / Origin x: 23.3384602018 Å / Origin y: 61.9292100992 Å / Origin z: 37.9276469469 Å
111213212223313233
T0.118553321524 Å20.0160580295269 Å2-0.0221709389905 Å2-0.12916632016 Å20.0212007623874 Å2--0.226634996107 Å2
L1.09705597255 °2-0.817349354163 °2-0.380820647822 °2-3.4571176893 °20.312120326506 °2--1.04144967575 °2
S-0.0596655322629 Å °-0.0159311996976 Å °-0.15280376853 Å °0.106991365552 Å °0.0547643044875 Å °0.525096867681 Å °0.0142512867028 Å °-0.0868365734353 Å °-0.0324224770811 Å °
Refinement TLS groupSelection details: all

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