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- PDB-9f2p: Crystal structure of Keap1 kelch domain in complex with a fluoren... -

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Basic information

Entry
Database: PDB / ID: 9f2p
TitleCrystal structure of Keap1 kelch domain in complex with a fluorenone-based small molecule inhibitor at 1.36A resolution
ComponentsKelch-like ECH-associated protein 1
KeywordsPEPTIDE BINDING PROTEIN / Keap1 / Nrf2 / Oxidative stress / Inhibitor
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body ...regulation of epidermal cell differentiation / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body / cellular response to interleukin-4 / actin filament / centriolar satellite / disordered domain specific binding / midbody / cellular response to oxidative stress / ubiquitin-dependent protein catabolic process / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / protein ubiquitination / regulation of autophagy / regulation of DNA-templated transcription / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / protein-containing complex / 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 motif / Kelch repeat type 1 / 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 motif / Kelch repeat type 1 / 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
: / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.36 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR366-2021-270 Denmark
Citation
Journal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors.
Authors: Qin, Y. / Poulsen, C. / Narayanan, D. / Chan, C.B. / Chen, X. / Montes, B.R. / Tran, K.T. / Mukminova, E. / Lin, C. / Gajhede, M. / Bullock, A.N. / Olagnier, D. / Bach, A.
#1: Journal: J Med Chem / Year: 2022
Title: Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery.
Authors: Narayanan, D. / Tran, K.T. / Pallesen, J.S. / Solbak, S.M.O. / Qin, Y. / Mukminova, E. / Luchini, M. / Vasilyeva, K.O. / Gonzalez Chichon, D. / Goutsiou, G. / Poulsen, C. / Haapanen, N. / ...Authors: Narayanan, D. / Tran, K.T. / Pallesen, J.S. / Solbak, S.M.O. / Qin, Y. / Mukminova, E. / Luchini, M. / Vasilyeva, K.O. / Gonzalez Chichon, D. / Goutsiou, G. / Poulsen, C. / Haapanen, N. / Popowicz, G.M. / Sattler, M. / Olagnier, D. / Gajhede, M. / Bach, A.
History
DepositionApr 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,47521
Polymers33,3621
Non-polymers2,11320
Water4,161231
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3150 Å2
ΔGint-29 kcal/mol
Surface area12770 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.119, 103.119, 55.266
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61
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


Mass: 33362.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Keap1, Inrf2, Kiaa0132
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9Z2X8
#2: Chemical ChemComp-A1H9C / (R)-2-(3-(((4-methoxyphenyl)sulfonamido)methyl)phenyl)-2-(9-oxo-9H-fluorene-4-carboxamido)acetate / (2~{R})-2-[3-[[(4-methoxyphenyl)sulfonylamino]methyl]phenyl]-2-[(9-oxidanylidenefluoren-4-yl)carbonylamino]ethanoic acid


Mass: 556.586 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C30H24N2O7S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 231 / Source method: isolated from a natural source / Formula: H2O
Has ligand of interestY
Has protein modificationN

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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: 2.67 Å3/Da / Density % sol: 53.92 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.5 M AMMONIUM SULFATE, 0.1 M SODIUM CITRATE TRIBASIC DIHYDRATE PH 5.6 AND 1.0 M LITHIUM SULFATE MONOHYDRATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9763 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Sep 23, 2022
RadiationMonochromator: Si (111), double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9763 Å / Relative weight: 1
ReflectionResolution: 1.36→46.99 Å / Num. obs: 71819 / % possible obs: 99.8 % / Redundancy: 20.3 % / Biso Wilson estimate: 20.97 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.088 / Rpim(I) all: 0.02 / Rrim(I) all: 0.09 / Χ2: 0.89 / Net I/σ(I): 16.6
Reflection shellResolution: 1.36→1.41 Å / % possible obs: 99.6 % / Redundancy: 18.4 % / Rmerge(I) obs: 2.65 / Num. measured all: 128866 / Num. unique obs: 6994 / CC1/2: 0.639 / Rpim(I) all: 0.628 / Rrim(I) all: 2.725 / Χ2: 0.71 / Net I/σ(I) obs: 1

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX(1.20.1_4487: ???)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.36→44.65 Å / SU ML: 0.17 / Cross valid method: FREE R-VALUE / σ(F): 1.35 / Phase error: 20.55 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.1745 3623 5.05 %
Rwork0.142 --
obs0.1437 71737 99.76 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 28.32 Å2
Refinement stepCycle: LAST / Resolution: 1.36→44.65 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2235 0 120 231 2586
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0082570
X-RAY DIFFRACTIONf_angle_d1.0233525
X-RAY DIFFRACTIONf_dihedral_angle_d6.694389
X-RAY DIFFRACTIONf_chiral_restr0.092358
X-RAY DIFFRACTIONf_plane_restr0.009465
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.36-1.380.43061480.41772562X-RAY DIFFRACTION98
1.38-1.40.34731570.33312533X-RAY DIFFRACTION99
1.4-1.420.31741450.29382593X-RAY DIFFRACTION99
1.42-1.440.29161480.25682583X-RAY DIFFRACTION100
1.44-1.460.2371990.22292666X-RAY DIFFRACTION99
1.46-1.480.22431160.20382621X-RAY DIFFRACTION100
1.48-1.510.22441600.18722568X-RAY DIFFRACTION99
1.51-1.540.21361080.17212669X-RAY DIFFRACTION100
1.54-1.570.2191450.16642580X-RAY DIFFRACTION100
1.57-1.60.20461280.13462611X-RAY DIFFRACTION100
1.6-1.630.18631340.13592638X-RAY DIFFRACTION100
1.63-1.670.19981450.12192624X-RAY DIFFRACTION100
1.67-1.710.16591360.12332595X-RAY DIFFRACTION100
1.71-1.760.15351330.11092606X-RAY DIFFRACTION100
1.76-1.810.16021470.1182631X-RAY DIFFRACTION100
1.81-1.870.1331430.11182616X-RAY DIFFRACTION100
1.87-1.940.15971410.12122621X-RAY DIFFRACTION100
1.94-2.010.14751320.10822651X-RAY DIFFRACTION100
2.01-2.110.15161350.12652610X-RAY DIFFRACTION100
2.11-2.220.16471460.11672640X-RAY DIFFRACTION100
2.22-2.360.15631440.13162607X-RAY DIFFRACTION100
2.36-2.540.19021360.13832653X-RAY DIFFRACTION100
2.54-2.790.18231410.14792647X-RAY DIFFRACTION100
2.79-3.20.17841630.1412610X-RAY DIFFRACTION100
3.2-4.030.1631400.13322669X-RAY DIFFRACTION100
4.03-44.650.16371530.14892710X-RAY DIFFRACTION100

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