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- PDB-6sp1: KEAP1 IN COMPLEX WITH COMPOUND 6 -

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Basic information

Entry
Database: PDB / ID: 6sp1
TitleKEAP1 IN COMPLEX WITH COMPOUND 6
ComponentsKelch-like ECH-associated protein 1
KeywordsPROTEIN BINDING / NRF2 / KEAP1 / protein-protein interactions / Huntingtons disease / tetrahydroisoquinoline
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / 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 / negative regulation of DNA-binding transcription factor activity ...regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / 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 / negative regulation of DNA-binding transcription factor activity / KEAP1-NFE2L2 pathway / disordered domain specific binding / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Antigen processing: Ubiquitination & Proteasome degradation / cellular response to oxidative stress / Neddylation / midbody / ubiquitin-dependent protein catabolic process / in utero embryonic development / RNA polymerase II-specific DNA-binding transcription factor binding / Potential therapeutics for SARS / protein ubiquitination / Ub-specific processing proteases / endoplasmic reticulum / 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
ACETATE ION / Chem-LQ8 / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.57 Å
AuthorsOntoria, J.M. / Biancofiore, I. / Fezzardi, P. / Torrente de Haro, E. / Colarusso, S. / Bianchi, E. / Andreini, M. / Patsilinakos, A. / Summa, V. / Pacifici, R. ...Ontoria, J.M. / Biancofiore, I. / Fezzardi, P. / Torrente de Haro, E. / Colarusso, S. / Bianchi, E. / Andreini, M. / Patsilinakos, A. / Summa, V. / Pacifici, R. / Munoz-Sanjuan, I. / Park, L. / Bresciani, A. / Dominguez, C. / Toledo-Sherman, L. / Harper, S.
CitationJournal: Acs Med.Chem.Lett. / Year: 2020
Title: Combined Peptide and Small-Molecule Approach toward Nonacidic THIQ Inhibitors of the KEAP1/NRF2 Interaction.
Authors: Ontoria, J.M. / Biancofiore, I. / Fezzardi, P. / Ferrigno, F. / Torrente, E. / Colarusso, S. / Bianchi, E. / Andreini, M. / Patsilinakos, A. / Kempf, G. / Augustin, M. / Steinbacher, S. / ...Authors: Ontoria, J.M. / Biancofiore, I. / Fezzardi, P. / Ferrigno, F. / Torrente, E. / Colarusso, S. / Bianchi, E. / Andreini, M. / Patsilinakos, A. / Kempf, G. / Augustin, M. / Steinbacher, S. / Summa, V. / Pacifici, R. / Munoz-Sanjuan, I. / Park, L. / Bresciani, A. / Dominguez, C. / Sherman, L.T. / Harper, S.
History
DepositionAug 30, 2019Deposition site: PDBE / Processing site: PDBE
Revision 1.0Jun 3, 2020Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

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Assembly

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


Theoretical massNumber of molelcules
Total (without water)65,29618
Polymers63,9042
Non-polymers1,39216
Water3,117173
1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,99011
Polymers31,9521
Non-polymers1,03810
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
2
B: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,3067
Polymers31,9521
Non-polymers3546
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)76.164, 76.387, 204.839
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

#1: Protein Kelch-like ECH-associated protein 1 / Cytosolic inhibitor of Nrf2 / INrf2 / Kelch-like protein 19


Mass: 31951.773 Da / Num. of mol.: 2 / Fragment: KELCH DOMAIN, RESIDUES 321-609
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Chemical ChemComp-LQ8 / (1~{S},2~{R})-2-[[(1~{S})-1-[[1,3-bis(oxidanylidene)isoindol-2-yl]methyl]-5-(2-hydroxyethyloxy)-3,4-dihydro-1~{H}-isoquinolin-2-yl]carbonyl]cyclohexane-1-carboxylic acid


Mass: 506.547 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C28H30N2O7 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 15 / Source method: obtained synthetically / Formula: C2H3O2
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 173 / 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: 4.65 Å3/Da / Density % sol: 73.54 %
Crystal growTemperature: 277 K / Method: vapor diffusion, hanging drop / Details: ammonium acetate

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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 2M / Detector: PIXEL / Date: Feb 18, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
ReflectionResolution: 2.57→102.42 Å / Num. obs: 36564 / % possible obs: 94 % / Redundancy: 3.3 % / Biso Wilson estimate: 53.053 Å2 / CC1/2: 0.998 / Rmerge(I) obs: 0.06 / Rrim(I) all: 0.07 / Χ2: 1.064 / Net I/σ(I): 14.62
Reflection shellResolution: 2.57→2.82 Å / Redundancy: 3.5 % / Rmerge(I) obs: 0.436 / Mean I/σ(I) obs: 14.62 / Num. unique obs: 194 / CC1/2: 1 / Rrim(I) all: 0.016 / % possible all: 94

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.2.0005refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.57→102.42 Å / Cor.coef. Fo:Fc: 0.948 / Cor.coef. Fo:Fc free: 0.945 / SU B: 14.309 / SU ML: 0.152 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.275 / ESU R Free: 0.205
Details: U VALUES : WITH TLS ADDED HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.2156 905 2.5 %RANDOM
Rwork0.2005 ---
obs0.2009 35659 94.06 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 85.37 Å2 / Biso mean: 53.303 Å2 / Biso min: 2 Å2
Baniso -1Baniso -2Baniso -3
1-0.42 Å20 Å20 Å2
2---1.52 Å20 Å2
3---1.1 Å2
Refinement stepCycle: final / Resolution: 2.57→102.42 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4372 0 97 174 4643
Biso mean--59.67 46.39 -
Num. residues----570
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.0214541
X-RAY DIFFRACTIONr_bond_other_d0.0020.023990
X-RAY DIFFRACTIONr_angle_refined_deg1.0441.9526177
X-RAY DIFFRACTIONr_angle_other_deg0.86339171
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.4045568
X-RAY DIFFRACTIONr_dihedral_angle_2_deg31.09522.464207
X-RAY DIFFRACTIONr_dihedral_angle_3_deg10.88515642
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.771542
X-RAY DIFFRACTIONr_chiral_restr0.0680.2655
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.025245
X-RAY DIFFRACTIONr_gen_planes_other0.0010.02991
X-RAY DIFFRACTIONr_nbd_refined0.1410.2559
X-RAY DIFFRACTIONr_nbd_other0.1360.23910
X-RAY DIFFRACTIONr_nbtor_refined0.1530.22064
X-RAY DIFFRACTIONr_nbtor_other0.0640.22496
X-RAY DIFFRACTIONr_xyhbond_nbd_refined0.0640.2168
X-RAY DIFFRACTIONr_symmetry_vdw_refined0.0510.21
X-RAY DIFFRACTIONr_symmetry_vdw_other0.1110.224
X-RAY DIFFRACTIONr_symmetry_hbond_refined0.0850.25
LS refinement shellResolution: 2.571→2.638 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.43 45 -
Rwork0.35 2593 -
obs--92.89 %
Refinement TLS params.

Method: refined / Origin x: 0 Å / Origin y: 0 Å / Origin z: 0 Å / Refine-ID: X-RAY DIFFRACTION

IDL11 (°2)L12 (°2)L13 (°2)L22 (°2)L23 (°2)L33 (°2)S11 (Å °)S12 (Å °)S13 (Å °)S21 (Å °)S22 (Å °)S23 (Å °)S31 (Å °)S32 (Å °)S33 (Å °)T11 (Å2)T12 (Å2)T13 (Å2)T22 (Å2)T23 (Å2)T33 (Å2)
12.2992-0.24940.05612.8878-0.00271.43330.01240.0823-0.0269-0.05670.00520.14240.1199-0.1247-0.01750.07090.00440.07440.01880.02270.1154
22.5869-0.30820.04321.99410.07141.8213-0.0911-0.04510.11690.10320.0349-0.0302-0.09010.02670.05610.03080.01180.02720.12920.09020.1156
Refinement TLS group
IDRefine-IDRefine TLS-IDAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1A325 - 609
2X-RAY DIFFRACTION2B325 - 609

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