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- PDB-6zez: Keap1 kelch domain bound to a small molecule inhibitor of the Kea... -

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Basic information

Entry
Database: PDB / ID: 6zez
TitleKeap1 kelch domain bound to a small molecule inhibitor of the Keap1-Nrf2 protein-protein interaction
ComponentsKelch-like ECH-associated protein 1
KeywordsPEPTIDE BINDING PROTEIN / Keap1 / Nrf2 / Oxidative stress / Small molecule complex
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 / cellular response to oxidative stress / midbody / 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 / regulation of autophagy / protein ubiquitination / 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 motif / Kelch / 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 motif / Kelch / 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
Chem-QHH / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.55 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR190-2014-3710 Denmark
Citation
Journal: J.Med.Chem. / Year: 2021
Title: Deconstructing Noncovalent Kelch-like ECH-Associated Protein 1 (Keap1) Inhibitors into Fragments to Reconstruct New Potent Compounds.
Authors: Pallesen, J.S. / Narayanan, D. / Tran, K.T. / Solbak, S.M.O. / Marseglia, G. / Sorensen, L.M.E. / Hoj, L.J. / Munafo, F. / Carmona, R.M.C. / Garcia, A.D. / Desu, H.L. / Brambilla, R. / ...Authors: Pallesen, J.S. / Narayanan, D. / Tran, K.T. / Solbak, S.M.O. / Marseglia, G. / Sorensen, L.M.E. / Hoj, L.J. / Munafo, F. / Carmona, R.M.C. / Garcia, A.D. / Desu, H.L. / Brambilla, R. / Johansen, T.N. / Popowicz, G.M. / Sattler, M. / Gajhede, M. / Bach, A.
History
DepositionJun 16, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 14, 2021Provider: repository / Type: Initial release
Revision 1.1May 5, 2021Group: 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
Revision 1.2Jan 24, 2024Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession

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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)33,8262
Polymers33,3621
Non-polymers4641
Water181
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area0 Å2
ΔGint0 kcal/mol
Surface area11900 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.684, 103.684, 55.029
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


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-QHH / 1-[3-[(1~{R},3~{S})-3-[(2~{S})-2-butylpyrrolidin-1-yl]carbonylcyclohexyl]phenyl]-5-cyclopropyl-pyrazole-4-carboxylic acid


Mass: 463.612 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H37N3O3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 1 / 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: 2.7 Å3/Da / Density % sol: 54.55 %
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: ESRF / Beamline: ID29 / Wavelength: 1.0723 Å
DetectorType: DECTRIS PILATUS 6M-F / Detector: PIXEL / Date: Oct 24, 2018 / Details: Toroidal mirror
RadiationMonochromator: Si(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.0723 Å / Relative weight: 1
ReflectionResolution: 2.55→44.9 Å / Num. obs: 21574 / % possible obs: 99.86 % / Redundancy: 5.7 % / Biso Wilson estimate: 59.96 Å2 / CC1/2: 0.993 / Rmerge(I) obs: 0.1867 / Rpim(I) all: 0.08615 / Rrim(I) all: 0.2059 / Net I/σ(I): 6.74
Reflection shellResolution: 2.55→2.641 Å / Redundancy: 5.4 % / Rmerge(I) obs: 1.968 / Mean I/σ(I) obs: 0.69 / Num. unique obs: 2159 / CC1/2: 0.389 / Rpim(I) all: 0.9285 / Rrim(I) all: 2.18 / % possible all: 99.08

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Processing

Software
NameVersionClassification
XDSv Jan 26, 2018data reduction
XDSv Jan 26, 2018data scaling
PHASER1.13-2998phasing
PHENIX1.13-2998refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5FNU

5fnu


Resolution: 2.55→44.9 Å / SU ML: 0.446 / Cross valid method: FREE R-VALUE / σ(F): 1.36 / Phase error: 32.3109 / Stereochemistry target values: GeoStd + Monomer Library
RfactorNum. reflection% reflectionSelection details
Rfree0.2535 1128 5.23 %Random
Rwork0.21 20429 --
obs0.2124 21556 99.88 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Displacement parametersBiso mean: 72.2 Å2
Refinement stepCycle: LAST / Resolution: 2.55→44.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 34 1 2254
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.00212323
X-RAY DIFFRACTIONf_angle_d0.54833167
X-RAY DIFFRACTIONf_chiral_restr0.0462333
X-RAY DIFFRACTIONf_plane_restr0.0028417
X-RAY DIFFRACTIONf_dihedral_angle_d13.01581361
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.55-2.670.38981320.35312583X-RAY DIFFRACTION99.27
2.67-2.810.35221230.33852558X-RAY DIFFRACTION100
2.81-2.980.31051600.28142526X-RAY DIFFRACTION100
2.98-3.210.26161160.27142580X-RAY DIFFRACTION99.93
3.21-3.540.29761440.23342556X-RAY DIFFRACTION100
3.54-4.050.25131600.19512541X-RAY DIFFRACTION100
4.05-5.10.18691420.15792552X-RAY DIFFRACTION99.96
5.1-44.90.24271510.17822533X-RAY DIFFRACTION99.96
Refinement TLS params.Method: refined / Origin x: 29.0227464022 Å / Origin y: 27.9342348838 Å / Origin z: 2.61334113982 Å
111213212223313233
T0.391678912598 Å20.0303521018439 Å20.0574973553345 Å2-0.394717038408 Å2-0.0135980879467 Å2--0.383426780151 Å2
L2.99753334944 °2-0.952983795041 °20.524396011624 °2-3.99073843712 °20.170564446823 °2--2.1577246116 °2
S0.0291790119493 Å °0.0623228353077 Å °0.0367729719502 Å °0.0350090930036 Å °0.0717338270365 Å °-0.343103678892 Å °0.0587645992888 Å °0.150817776533 Å °-0.0769912942573 Å °
Refinement TLS groupSelection details: (chain 'A' and resid 325 through 613)

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