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- PDB-6qmd: Small molecule inhibitor of the KEAP1-NRF2 protein-protein interaction -

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Basic information

Entry
Database: PDB / ID: 6qmd
TitleSmall molecule inhibitor of the KEAP1-NRF2 protein-protein interaction
ComponentsKelch-like ECH-associated protein 1
KeywordsPROTEIN BINDING / Protein ubiquitination / oxidative stress / kelch motif
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 / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / regulation of autophagy / protein ubiquitination / regulation of DNA-templated transcription / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / protein-containing complex / nucleoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
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 / 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. / 6 Propeller / Neuraminidase / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-J6N / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.94 Å
AuthorsDavies, T.G.
CitationJournal: J.Med.Chem. / Year: 2019
Title: Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) ...Title: Structure-Activity and Structure-Conformation Relationships of Aryl Propionic Acid Inhibitors of the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-Related Factor 2 (KEAP1/NRF2) Protein-Protein Interaction.
Authors: Heightman, T.D. / Callahan, J.F. / Chiarparin, E. / Coyle, J.E. / Griffiths-Jones, C. / Lakdawala, A.S. / McMenamin, R. / Mortenson, P.N. / Norton, D. / Peakman, T.M. / Rich, S.J. / ...Authors: Heightman, T.D. / Callahan, J.F. / Chiarparin, E. / Coyle, J.E. / Griffiths-Jones, C. / Lakdawala, A.S. / McMenamin, R. / Mortenson, P.N. / Norton, D. / Peakman, T.M. / Rich, S.J. / Richardson, C. / Rumsey, W.L. / Sanchez, Y. / Saxty, G. / Willems, H.M.G. / Wolfe 3rd, L. / Woolford, A.J. / Wu, Z. / Yan, H. / Kerns, J.K. / Davies, T.G.
History
DepositionFeb 7, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Apr 24, 2019Provider: repository / Type: Initial release
Revision 1.1May 22, 2019Group: Data collection / Database references
Category: citation / citation_author ...citation / citation_author / database_PDB_rev / database_PDB_rev_record / pdbx_database_proc
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.title / _citation_author.name
Revision 1.2May 15, 2024Group: Data collection / Database references / Category: chem_comp_atom / chem_comp_bond / database_2
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)35,9614
Polymers35,2511
Non-polymers7103
Water6,359353
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area250 Å2
ΔGint3 kcal/mol
Surface area11840 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.391, 103.391, 56.506
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

#1: Protein Kelch-like ECH-associated protein 1 / Cytosolic inhibitor of Nrf2 / INrf2


Mass: 35251.371 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(DE3) (bacteria) / References: UniProt: Q9Z2X8
#2: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#3: Chemical ChemComp-J6N / (3~{R})-3-(4-chlorophenyl)-3-(1-methylbenzotriazol-5-yl)propanoic acid


Mass: 315.754 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: C16H14ClN3O2 / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 353 / Source method: isolated from a natural source / Formula: H2O

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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: 2.47 Å3/Da / Density % sol: 50.27 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.3M (NH4)2SO4 1M Li2SO4 0.1M pH=5.6 Na3 citrate/HCl

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: ROTATING ANODE / Type: RIGAKU FR-X / Wavelength: 1.54178 Å
DetectorType: RIGAKU SATURN 944 / Detector: CCD / Date: Feb 1, 2012
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.94→47.78 Å / Num. obs: 25770 / % possible obs: 97.1 % / Redundancy: 2.1 % / Rrim(I) all: 0.055 / Net I/σ(I): 10.9
Reflection shellResolution: 1.94→1.99 Å / Rmerge(I) obs: 0.151 / % possible all: 88.3

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
XDSdata reduction
SAINTdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.94→38.17 Å / Cor.coef. Fo:Fc: 0.964 / Cor.coef. Fo:Fc free: 0.949 / SU B: 5.622 / SU ML: 0.086 / Cross valid method: THROUGHOUT / ESU R: 0.137 / ESU R Free: 0.128 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19255 1269 5.1 %RANDOM
Rwork0.15377 ---
obs0.15575 23770 97.16 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 25.016 Å2
Baniso -1Baniso -2Baniso -3
1--0.36 Å2-0.18 Å2-0 Å2
2---0.36 Å20 Å2
3---1.16 Å2
Refinement stepCycle: 1 / Resolution: 1.94→38.17 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 48 353 2620
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0152347
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171961
X-RAY DIFFRACTIONr_angle_refined_deg1.3231.7443205
X-RAY DIFFRACTIONr_angle_other_deg0.4791.7174597
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.7065298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg25.97319.478115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.72815.095315
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.0811521
X-RAY DIFFRACTIONr_chiral_restr0.0630.2288
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.022741
X-RAY DIFFRACTIONr_gen_planes_other00.02459
X-RAY DIFFRACTIONr_nbd_refined
X-RAY DIFFRACTIONr_nbd_other
X-RAY DIFFRACTIONr_nbtor_refined
X-RAY DIFFRACTIONr_nbtor_other
X-RAY DIFFRACTIONr_xyhbond_nbd_refined
X-RAY DIFFRACTIONr_xyhbond_nbd_other
X-RAY DIFFRACTIONr_metal_ion_refined
X-RAY DIFFRACTIONr_metal_ion_other
X-RAY DIFFRACTIONr_symmetry_vdw_refined
X-RAY DIFFRACTIONr_symmetry_vdw_other
X-RAY DIFFRACTIONr_symmetry_hbond_refined
X-RAY DIFFRACTIONr_symmetry_hbond_other
X-RAY DIFFRACTIONr_symmetry_metal_ion_refined
X-RAY DIFFRACTIONr_symmetry_metal_ion_other
X-RAY DIFFRACTIONr_mcbond_it1.0822.0221165
X-RAY DIFFRACTIONr_mcbond_other1.0842.0271166
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.1362.7171182
X-RAY DIFFRACTIONr_scbond_other2.1362.7211183
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined5.66812.5562562
X-RAY DIFFRACTIONr_long_range_B_other5.5711.8962521
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.937→1.987 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.223 78 -
Rwork0.196 1546 -
obs--85.56 %
Refinement TLS params.Method: refined / Origin x: 22.8663 Å / Origin y: 61.5043 Å / Origin z: 37.9732 Å
111213212223313233
T0.033 Å20.0038 Å2-0.0158 Å2-0.0063 Å20.0048 Å2--0.0447 Å2
L2.4782 °2-0.4418 °2-0.5812 °2-2.9924 °20.4688 °2--1.4018 °2
S-0.0588 Å °-0.0382 Å °-0.0885 Å °0.181 Å °0.0323 Å °0.1538 Å °0.0266 Å °0.0331 Å °0.0265 Å °

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