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

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Basic information

Entry
Database: PDB / ID: 6qmc
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


cellular response to carbohydrate stimulus / KEAP1-NFE2L2 pathway / regulation of epidermal cell differentiation / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / centriolar satellite / inclusion body ...cellular response to carbohydrate stimulus / KEAP1-NFE2L2 pathway / regulation of epidermal cell differentiation / Neddylation / Antigen processing: Ubiquitination & Proteasome degradation / Ub-specific processing proteases / 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 / adherens junction / disordered domain specific binding / cellular response to oxidative stress / midbody / ubiquitin-dependent protein catabolic process / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / protein ubiquitination / negative regulation of gene expression / focal adhesion / regulation of DNA-templated transcription / 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 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 / 6 Propeller / Neuraminidase / SKP1/BTB/POZ domain superfamily / Mainly Beta
Similarity search - Domain/homology
Chem-J6H / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / FOURIER SYNTHESIS / Resolution: 1.77 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

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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)35,5292
Polymers35,2511
Non-polymers2781
Water6,593366
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 area11970 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.807, 103.807, 56.548
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-J6H / (3~{S})-3-(4-chlorophenyl)-3-(2-oxidanylidene-1~{H}-pyridin-4-yl)propanoic acid


Mass: 277.703 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C14H12ClNO3 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 366 / 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: 2.5 Å3/Da / Density % sol: 50.7 %
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: DECTRIS EIGER X 1M / Detector: PIXEL / Date: Mar 29, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.54178 Å / Relative weight: 1
ReflectionResolution: 1.77→89.9 Å / Num. obs: 34167 / % possible obs: 99.9 % / Redundancy: 8.9 % / Rrim(I) all: 0.073 / Net I/σ(I): 18.2
Reflection shellResolution: 1.77→1.78 Å / Mean I/σ(I) obs: 1.7 / Num. unique obs: 3008 / Rrim(I) all: 0.985 / % possible all: 98.4

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Processing

Software
NameVersionClassification
REFMAC5.8.0222refinement
XDSdata reduction
Aimlessdata scaling
REFMACphasing
RefinementMethod to determine structure: FOURIER SYNTHESIS / Resolution: 1.77→89.9 Å / Cor.coef. Fo:Fc: 0.973 / Cor.coef. Fo:Fc free: 0.96 / SU B: 4.565 / SU ML: 0.074 / Cross valid method: THROUGHOUT / ESU R: 0.099 / ESU R Free: 0.1 / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.19505 1745 5.1 %RANDOM
Rwork0.1584 ---
obs0.16028 32395 99.92 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso mean: 30.496 Å2
Baniso -1Baniso -2Baniso -3
1--0.22 Å2-0.11 Å2-0 Å2
2---0.22 Å20 Å2
3---0.71 Å2
Refinement stepCycle: 1 / Resolution: 1.77→89.9 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2219 0 19 366 2604
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0090.0152318
X-RAY DIFFRACTIONr_bond_other_d0.0010.0171942
X-RAY DIFFRACTIONr_angle_refined_deg1.381.7493163
X-RAY DIFFRACTIONr_angle_other_deg0.5111.7284558
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.5345298
X-RAY DIFFRACTIONr_dihedral_angle_2_deg26.68719.478115
X-RAY DIFFRACTIONr_dihedral_angle_3_deg12.15415.047316
X-RAY DIFFRACTIONr_dihedral_angle_4_deg19.8721521
X-RAY DIFFRACTIONr_chiral_restr0.0650.2288
X-RAY DIFFRACTIONr_gen_planes_refined0.0010.0212715
X-RAY DIFFRACTIONr_gen_planes_other00.02453
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_it1.5483.0961165
X-RAY DIFFRACTIONr_mcbond_other1.5513.1041166
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_mcangle_other
X-RAY DIFFRACTIONr_scbond_it2.8613.8591153
X-RAY DIFFRACTIONr_scbond_other2.863.8611154
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_scangle_other
X-RAY DIFFRACTIONr_long_range_B_refined6.05617.6942449
X-RAY DIFFRACTIONr_long_range_B_other5.84716.9982411
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 1.767→1.813 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.289 141 -
Rwork0.255 2353 -
obs--99.28 %
Refinement TLS params.Method: refined / Origin x: 22.8864 Å / Origin y: 61.7473 Å / Origin z: 37.9578 Å
111213212223313233
T0.0304 Å20.0064 Å2-0.0186 Å2-0.0047 Å20.0016 Å2--0.0562 Å2
L2.3508 °2-0.443 °2-0.5135 °2-3.1817 °20.4551 °2--1.3485 °2
S-0.0544 Å °-0.0377 Å °-0.0881 Å °0.167 Å °0.0416 Å °0.1821 Å °0.0442 Å °0.0299 Å °0.0128 Å °

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