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

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Basic information

Entry
Database: PDB / ID: 8ivr
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 / 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
Chem-SIU / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.5 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
DepositionMar 28, 2023Deposition site: PDBJ / Processing site: PDBJ
Revision 1.0Jun 14, 2023Provider: repository / Type: Initial release
Revision 1.1May 29, 2024Group: Data collection / Category: chem_comp_atom / chem_comp_bond

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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)35,5767
Polymers34,7301
Non-polymers8466
Water5,332296
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area230 Å2
ΔGint-18 kcal/mol
Surface area12240 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.911, 103.911, 54.425
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-SIU / (2R,3S)-2-methyl-3-(4-methylphenyl)-3-[2-(5,6,7,8-tetrahydronaphthalen-2-yl)ethanoylamino]propanoic acid


Mass: 365.465 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H27NO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


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


Mass: 18.015 Da / Num. of mol.: 296 / 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: 2.44 Å3/Da / Density % sol: 49.64 %
Crystal growTemperature: 277 K / Method: vapor diffusion / pH: 7.5
Details: hKEAP1 was concentrated to 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- ...Details: hKEAP1 was concentrated to 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: SLS / Beamline: X06SA / Wavelength: 1 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Apr 10, 2014
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 1.5→89.99 Å / Num. obs: 52857 / % possible obs: 98.4 % / Redundancy: 8.9 % / Rmerge(I) obs: 0.082 / Net I/av σ(I): 3.2 / Net I/σ(I): 17.1
Reflection shellResolution: 1.5→1.54 Å / Rmerge(I) obs: 0.351 / Mean I/σ(I) obs: 4 / Num. unique obs: 3800

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Processing

Software
NameVersionClassification
PHENIX1.20_4459refinement
XDSdata reduction
Aimlessdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.5→89.99 Å / SU ML: 0.1834 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 21.3417
Stereochemistry target values: GeoStd + Monomer Library + CDL v1.2
RfactorNum. reflection% reflection
Rfree0.1979 2662 5.08 %
Rwork0.1816 49741 -
obs0.1824 52403 97.56 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 30.5 Å2
Refinement stepCycle: LAST / Resolution: 1.5→89.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2251 0 52 296 2599
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00212384
X-RAY DIFFRACTIONf_angle_d0.55383255
X-RAY DIFFRACTIONf_chiral_restr0.0495339
X-RAY DIFFRACTIONf_plane_restr0.0049428
X-RAY DIFFRACTIONf_dihedral_angle_d10.863850
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.5-1.530.40041380.36482467X-RAY DIFFRACTION92.64
1.53-1.560.32981380.31472516X-RAY DIFFRACTION94.65
1.56-1.590.3061470.28232506X-RAY DIFFRACTION94.55
1.59-1.620.24741400.25132553X-RAY DIFFRACTION95.6
1.62-1.660.23221220.21852566X-RAY DIFFRACTION96.52
1.66-1.70.21211220.2032597X-RAY DIFFRACTION95.67
1.7-1.750.2191380.20892600X-RAY DIFFRACTION97.23
1.75-1.80.24631480.20372583X-RAY DIFFRACTION97.57
1.8-1.860.21851440.2182628X-RAY DIFFRACTION97.81
1.86-1.920.21481480.20342605X-RAY DIFFRACTION98.22
1.92-20.20481340.17632654X-RAY DIFFRACTION98.34
2-2.090.1951490.16692627X-RAY DIFFRACTION98.4
2.09-2.20.20921580.16792618X-RAY DIFFRACTION99.18
2.2-2.340.19311320.17562671X-RAY DIFFRACTION99.29
2.34-2.520.20371340.18532679X-RAY DIFFRACTION99.08
2.52-2.780.19331400.17632680X-RAY DIFFRACTION99.47
2.78-3.180.19091470.17352701X-RAY DIFFRACTION99.68
3.18-40.1751360.15762722X-RAY DIFFRACTION99.93
4-89.990.17121470.17052768X-RAY DIFFRACTION99.9
Refinement TLS params.Method: refined / Origin x: 23.135 Å / Origin y: 62.057 Å / Origin z: 37.953 Å
111213212223313233
T0.152271315417 Å20.0163312322711 Å2-0.0679765510257 Å2-0.159712843876 Å20.0113356526612 Å2--0.113972473757 Å2
L1.47418509712 °2-0.00874610542977 °2-0.531940696696 °2-4.49018273453 °20.0490400814698 °2--1.18687812292 °2
S-0.0451000650192 Å °0.0234621501198 Å °-0.0050246420577 Å °0.0617309862185 Å °0.0725275555108 Å °0.508852219618 Å °0.0263389711154 Å °-0.143114996433 Å °0.0216201641124 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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