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- PDB-4l7b: Structure of keap1 kelch domain with (1S,2R)-2-{[(1S)-1-[(1,3-dio... -

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Basic information

Entry
Database: PDB / ID: 4l7b
TitleStructure of keap1 kelch domain with (1S,2R)-2-{[(1S)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclohexanecarboxylic acid
ComponentsKelch-like ECH-associated protein 1
KeywordsTRANSCRIPTION/INHIBITOR / STRESS SENSOR / KELCH DOMAIN / KELCH REPEAT MOTIF / BETA-PROPELLER / NRF2 / PROTEIN-SMALL MOLECULE COMPLEX / TRANSCRIPTION-INHIBITOR complex
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-1VV / ACETATE ION / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.41 Å
AuthorsJnoff, E. / Brookfield, F. / Albrecht, C. / Barker, J.J. / Barker, O. / Beaumont, E. / Bromidge, S. / Brooks, M. / Ceska, T. / Courade, J.P. ...Jnoff, E. / Brookfield, F. / Albrecht, C. / Barker, J.J. / Barker, O. / Beaumont, E. / Bromidge, S. / Brooks, M. / Ceska, T. / Courade, J.P. / Crabbe, T. / Duclos, S. / Fryatt, T. / Jigorel, E. / Kwong, J. / Sands, Z. / Smith, M.A.
CitationJournal: Chemmedchem / Year: 2014
Title: Binding Mode and Structure-Activity Relationships around Direct Inhibitors of the Nrf2-Keap1 Complex.
Authors: Jnoff, E. / Albrecht, C. / Barker, J.J. / Barker, O. / Beaumont, E. / Bromidge, S. / Brookfield, F. / Brooks, M. / Bubert, C. / Ceska, T. / Corden, V. / Dawson, G. / Duclos, S. / Fryatt, T. ...Authors: Jnoff, E. / Albrecht, C. / Barker, J.J. / Barker, O. / Beaumont, E. / Bromidge, S. / Brookfield, F. / Brooks, M. / Bubert, C. / Ceska, T. / Corden, V. / Dawson, G. / Duclos, S. / Fryatt, T. / Genicot, C. / Jigorel, E. / Kwong, J. / Maghames, R. / Mushi, I. / Pike, R. / Sands, Z.A. / Smith, M.A. / Stimson, C.C. / Courade, J.P.
History
DepositionJun 13, 2013Deposition site: RCSB / Processing site: RCSB
Revision 1.0Feb 19, 2014Provider: repository / Type: Initial release
Revision 1.1Apr 23, 2014Group: Database references
Revision 1.2Sep 20, 2023Group: Data collection / Database references ...Data collection / Database references / Derived calculations / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model / struct_conn / struct_ref_seq_dif / struct_site
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _struct_conn.ptnr1_auth_asym_id / _struct_conn.ptnr1_auth_comp_id / _struct_conn.ptnr1_auth_seq_id / _struct_conn.ptnr1_label_asym_id / _struct_conn.ptnr1_label_atom_id / _struct_conn.ptnr1_label_comp_id / _struct_conn.ptnr2_auth_asym_id / _struct_conn.ptnr2_auth_comp_id / _struct_conn.ptnr2_auth_seq_id / _struct_conn.ptnr2_label_asym_id / _struct_conn.ptnr2_label_atom_id / _struct_conn.ptnr2_label_comp_id / _struct_ref_seq_dif.details / _struct_site.pdbx_auth_asym_id / _struct_site.pdbx_auth_comp_id / _struct_site.pdbx_auth_seq_id

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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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)66,7849
Polymers66,0202
Non-polymers7657
Water4,288238
1


  • Idetical with deposited unit
  • defined by author&software
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area1300 Å2
ΔGint-2 kcal/mol
Surface area23950 Å2
MethodPISA
Unit cell
Length a, b, c (Å)75.760, 75.850, 205.370
Angle α, β, γ (deg.)90.00, 90.00, 90.00
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: 33009.801 Da / Num. of mol.: 2 / Fragment: Kelch domain, UNP residues 321-609 / Mutation: R354D
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Plasmid: pET28a / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Chemical
ChemComp-ACT / ACETATE ION / Acetate


Mass: 59.044 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: C2H3O2
#3: Chemical ChemComp-1VV / (1S,2R)-2-{[(1S)-1-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]-3,4-dihydroisoquinolin-2(1H)-yl]carbonyl}cyclohexanecarboxylic acid


Mass: 446.495 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H26N2O5
#4: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 238 / 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: 4.47 Å3/Da / Density % sol: 72.48 %
Crystal growTemperature: 296 K / Method: vapor diffusion, hanging drop / pH: 4.6
Details: 1 ul of protein at 12 mg/ml in 20 mM Tris-HCl pH 7.5, 5 mM DTT, 5 mM compound 1 + 2 ul of 2.15 M Sodium Acetate , VAPOR DIFFUSION, HANGING DROP, temperature 296K

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: Diamond / Beamline: I02 / Wavelength: 0.9795 Å
DetectorType: DECTRIS PILATUS 6M / Detector: PIXEL / Date: Sep 19, 2012 / Details: Mirrors
RadiationMonochromator: Double Crystal Monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9795 Å / Relative weight: 1
ReflectionResolution: 2.41→75.37 Å / Num. all: 46220 / Num. obs: 46220 / % possible obs: 99.6 % / Observed criterion σ(F): 2 / Observed criterion σ(I): 2 / Biso Wilson estimate: 62.774 Å2 / Rmerge(I) obs: 0.064
Reflection shellResolution: 2.41→2.47 Å / % possible all: 99.71

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Processing

Software
NameVersionClassification
GDAdata collection
PHASERphasing
REFMAC5.7.0032refinement
XDSdata reduction
XDSdata scaling
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB ENTRY 1ZGK

1zgk


Resolution: 2.41→60.96 Å / Cor.coef. Fo:Fc: 0.937 / Cor.coef. Fo:Fc free: 0.927 / SU B: 7.271 / SU ML: 0.161 / Cross valid method: THROUGHOUT / ESU R: 0.247 / ESU R Free: 0.2 / Stereochemistry target values: MAXIMUM LIKELIHOOD / Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS
RfactorNum. reflection% reflectionSelection details
Rfree0.24602 2342 5.1 %RANDOM
Rwork0.22851 ---
all0.22938 46334 --
obs0.22938 43927 99.22 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso mean: 51.371 Å2
Baniso -1Baniso -2Baniso -3
1--0.24 Å2-0 Å20 Å2
2---0.05 Å2-0 Å2
3---0.29 Å2
Refinement stepCycle: LAST / Resolution: 2.41→60.96 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4485 0 54 238 4777
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0040.0194674
X-RAY DIFFRACTIONr_bond_other_d0.0010.024235
X-RAY DIFFRACTIONr_angle_refined_deg0.8891.9456372
X-RAY DIFFRACTIONr_angle_other_deg0.739688
X-RAY DIFFRACTIONr_dihedral_angle_1_deg5.0655589
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.27222.838222
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.62215683
X-RAY DIFFRACTIONr_dihedral_angle_4_deg13.831542
X-RAY DIFFRACTIONr_chiral_restr0.0510.2675
X-RAY DIFFRACTIONr_gen_planes_refined0.0020.0215495
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021162
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_it
X-RAY DIFFRACTIONr_mcbond_other
X-RAY DIFFRACTIONr_mcangle_it
X-RAY DIFFRACTIONr_scbond_it
X-RAY DIFFRACTIONr_scangle_it
X-RAY DIFFRACTIONr_rigid_bond_restr
X-RAY DIFFRACTIONr_sphericity_free
X-RAY DIFFRACTIONr_sphericity_bonded
LS refinement shellResolution: 2.41→2.473 Å / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.385 179 -
Rwork0.371 3218 -
obs--99.71 %

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