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- PDB-6sp4: KEAP1 IN COMPLEX WITH COMPOUND 23 -

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Basic information

Entry
Database: PDB / ID: 6sp4
TitleKEAP1 IN COMPLEX WITH COMPOUND 23
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
Chem-LQK / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.59 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
C: Kelch-like ECH-associated protein 1
D: Kelch-like ECH-associated protein 1
E: Kelch-like ECH-associated protein 1
F: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)194,57612
Polymers191,7116
Non-polymers2,8656
Water3,963220
1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4292
Polymers31,9521
Non-polymers4781
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)32,4292
Polymers31,9521
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4292
Polymers31,9521
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4292
Polymers31,9521
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
5
E: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4292
Polymers31,9521
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
6
F: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,4292
Polymers31,9521
Non-polymers4781
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)112.452, 91.875, 112.313
Angle α, β, γ (deg.)90.000, 119.890, 90.000
Int Tables number4
Space group name H-MP1211

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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.: 6 / 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-LQK / (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]cyclobutane-1-carboxamide


Mass: 477.509 Da / Num. of mol.: 6 / Source method: obtained synthetically / Formula: C26H27N3O6 / Feature type: SUBJECT OF INVESTIGATION
#3: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 220 / 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: 2.62 Å3/Da / Density % sol: 53.15 %
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 EIGER X 16M / Detector: PIXEL / Date: Oct 14, 2015
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1 Å / Relative weight: 1
Reflection twin
Crystal-IDIDOperatorDomain-IDFraction
11H, K, L10.381
11H+L, -K, -L20.152
11L, -K, H30.231
11L, K, -H-L40.11
11-H-L, K, H50.036
11-H, -K, H+L60.09
ReflectionResolution: 2.59→47.99 Å / Num. obs: 59516 / % possible obs: 97 % / Redundancy: 2.9 % / Rmerge(I) obs: 0.083 / Net I/σ(I): 10.8
Reflection shellResolution: 2.6→2.805 Å / Redundancy: 3 % / Rmerge(I) obs: 0.431 / Mean I/σ(I) obs: 2.69 / Num. unique obs: 12142 / % possible all: 97.8

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Processing

Software
NameVersionClassification
XSCALEdata scaling
REFMAC5.8.0049refinement
PDB_EXTRACT3.25data extraction
XDSdata reduction
MOLREPphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: NONE

Resolution: 2.59→47.99 Å / Cor.coef. Fo:Fc: 0.946 / Cor.coef. Fo:Fc free: 0.942 / SU B: 13.275 / SU ML: 0.301 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.171 / ESU R Free: 0.061
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2247 894 1.5 %RANDOM
Rwork0.1749 ---
obs0.1757 58621 96.58 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 174.5 Å2 / Biso mean: 63.709 Å2 / Biso min: 7.29 Å2
Baniso -1Baniso -2Baniso -3
1--52.87 Å2-0 Å25.56 Å2
2--90.09 Å20 Å2
3----37.22 Å2
Refinement stepCycle: final / Resolution: 2.59→47.99 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms13101 0 210 220 13531
Biso mean--58.45 41.81 -
Num. residues----1707
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0080.01913656
X-RAY DIFFRACTIONr_bond_other_d0.0050.0212345
X-RAY DIFFRACTIONr_angle_refined_deg1.2561.95218626
X-RAY DIFFRACTIONr_angle_other_deg0.949328198
X-RAY DIFFRACTIONr_dihedral_angle_1_deg6.26451701
X-RAY DIFFRACTIONr_dihedral_angle_2_deg33.63522.453636
X-RAY DIFFRACTIONr_dihedral_angle_3_deg15.547151963
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.10615132
X-RAY DIFFRACTIONr_chiral_restr0.0750.21976
X-RAY DIFFRACTIONr_gen_planes_refined0.0040.02115945
X-RAY DIFFRACTIONr_gen_planes_other0.0020.023423
LS refinement shellResolution: 2.594→2.661 Å / Rfactor Rfree error: 0
RfactorNum. reflection% reflection
Rfree0.45 62 -
Rwork0.292 3809 -
obs--86.83 %

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