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- PDB-5who: Kelch domain of human Keap1 bound to small molecule inhibitor fra... -

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Basic information

Entry
Database: PDB / ID: 5who
TitleKelch domain of human Keap1 bound to small molecule inhibitor fragment: 4-oxo-4H-1-benzopyran-2-carboxylic acid
ComponentsKelch-like ECH-associated protein 1
KeywordsTRANSCRIPTION/INHIBITOR / Scaffold / Inhibitor / Fragment / TRANSCRIPTION / TRANSCRIPTION-INHIBITOR complex
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / centriolar satellite / ubiquitin-like ligase-substrate adaptor activity / cellular response to interleukin-4 / inclusion body / regulation of autophagy / actin filament ...regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / centriolar satellite / ubiquitin-like ligase-substrate adaptor activity / cellular response to interleukin-4 / inclusion body / regulation of autophagy / actin filament / negative regulation of DNA-binding transcription factor activity / disordered domain specific binding / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / cellular response to oxidative stress / midbody / ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / Potential therapeutics for SARS / Ub-specific processing proteases / protein ubiquitination / 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 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. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / 6 Propeller / Neuraminidase / SKP1/BTB/POZ domain superfamily / Mainly Beta
Similarity search - Domain/homology
4-oxo-4H-1-benzopyran-2-carboxylic acid / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 2.23 Å
AuthorsCarolan, J.P. / Lynch, A.J. / Allen, K.N.
Funding support United States, 1items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35-GM118078 United States
CitationJournal: Biochemistry / Year: 2020
Title: Interaction Energetics and Druggability of the Protein-Protein Interaction between Kelch-like ECH-Associated Protein 1 (KEAP1) and Nuclear Factor Erythroid 2 Like 2 (Nrf2).
Authors: Zhong, M. / Lynch, A. / Muellers, S.N. / Jehle, S. / Luo, L. / Hall, D.R. / Iwase, R. / Carolan, J.P. / Egbert, M. / Wakefield, A. / Streu, K. / Harvey, C.M. / Ortet, P.C. / Kozakov, D. / ...Authors: Zhong, M. / Lynch, A. / Muellers, S.N. / Jehle, S. / Luo, L. / Hall, D.R. / Iwase, R. / Carolan, J.P. / Egbert, M. / Wakefield, A. / Streu, K. / Harvey, C.M. / Ortet, P.C. / Kozakov, D. / Vajda, S. / Allen, K.N. / Whitty, A.
History
DepositionJul 17, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 19, 2018Provider: repository / Type: Initial release
Revision 1.1Jan 1, 2020Group: Author supporting evidence / Category: pdbx_audit_support / Item: _pdbx_audit_support.funding_organization
Revision 1.2Apr 1, 2020Group: Database references / Category: citation / citation_author
Item: _citation.country / _citation.journal_abbrev ..._citation.country / _citation.journal_abbrev / _citation.journal_id_ASTM / _citation.journal_id_CSD / _citation.journal_id_ISSN / _citation.journal_volume / _citation.page_first / _citation.page_last / _citation.pdbx_database_id_DOI / _citation.pdbx_database_id_PubMed / _citation.title / _citation.year
Revision 1.3Oct 4, 2023Group: Data collection / Database references / Refinement description
Category: chem_comp_atom / chem_comp_bond ...chem_comp_atom / chem_comp_bond / database_2 / pdbx_initial_refinement_model
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
B: Kelch-like ECH-associated protein 1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,3737
Polymers73,7982
Non-polymers5745
Water2,792155
1
B: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1874
Polymers36,8991
Non-polymers2883
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,1853
Polymers36,8991
Non-polymers2862
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)78.460, 69.090, 143.206
Angle α, β, γ (deg.)90.00, 91.11, 90.00
Int Tables number5
Space group name H-MI121

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Components

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


Mass: 36899.176 Da / Num. of mol.: 2 / Mutation: E540A, E542A
Source method: isolated from a genetically manipulated source
Details: His-tagged variant including mutations for altered crystallographic packing
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145
#2: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Formula: SO4
#3: Chemical ChemComp-AO7 / 4-oxo-4H-1-benzopyran-2-carboxylic acid / 9,10-SECOCHOLESTA-5,7,10(19)-TRIENE-1,3,25-TRIOL,2-(3-HYDROXYPROPOXY)-,(1A,2A,3B,5Z,7E)


Mass: 190.152 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C10H6O4
#4: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 155 / 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: 2.83 Å3/Da / Density % sol: 56.59 %
Crystal growTemperature: 290 K / Method: vapor diffusion, hanging drop
Details: 1.2 - 1.5 M Ammonium sulfate, 0.1 M Bis-Tris pH = 6.0 - 6.5
PH range: 6.0 - 6.5

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Data collection

DiffractionMean temperature: 100 K
Diffraction sourceSource: SYNCHROTRON / Site: NSLS / Beamline: X29A / Wavelength: 1.075 Å
DetectorType: ADSC QUANTUM 315 / Detector: CCD / Date: Jul 21, 2014
Details: 12 V servo motors utilizing a CAMAC-based E500 stepper controller
RadiationMonochromator: Double crystals monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.075 Å / Relative weight: 1
ReflectionResolution: 2.23→51.85 Å / Num. obs: 37484 / % possible obs: 96.55 % / Redundancy: 2 % / CC1/2: 0.998 / Rmerge(I) obs: 0.039 / Net I/σ(I): 12.62
Reflection shellResolution: 2.23→2.31 Å / Redundancy: 1.9 % / Rmerge(I) obs: 0.279 / Mean I/σ(I) obs: 2.85 / Num. unique obs: 3718 / CC1/2: 0.835 / % possible all: 89.38

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Processing

Software
NameVersionClassification
PHENIX(1.13_2998: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WFL

5wfl


Resolution: 2.23→51.848 Å / SU ML: 0.26 / Cross valid method: FREE R-VALUE / σ(F): 0 / Phase error: 24.01 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2372 1936 5.34 %Random selection
Rwork0.1958 ---
obs0.198 36243 96.56 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.23→51.848 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4357 0 34 155 4546
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074494
X-RAY DIFFRACTIONf_angle_d0.9616124
X-RAY DIFFRACTIONf_dihedral_angle_d6.1952582
X-RAY DIFFRACTIONf_chiral_restr0.058650
X-RAY DIFFRACTIONf_plane_restr0.005806
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.23-2.28580.28241280.23032212X-RAY DIFFRACTION88
2.2858-2.34760.29531270.22442328X-RAY DIFFRACTION92
2.3476-2.41660.24471290.22522353X-RAY DIFFRACTION93
2.4166-2.49460.28921340.23112355X-RAY DIFFRACTION93
2.4946-2.58380.25951390.22782388X-RAY DIFFRACTION96
2.5838-2.68730.2921370.22352464X-RAY DIFFRACTION96
2.6873-2.80950.26911370.20412476X-RAY DIFFRACTION98
2.8095-2.95770.2541370.20032454X-RAY DIFFRACTION98
2.9577-3.14290.23671470.20962523X-RAY DIFFRACTION99
3.1429-3.38560.21291360.19992508X-RAY DIFFRACTION99
3.3856-3.72620.21661460.18842536X-RAY DIFFRACTION100
3.7262-4.26520.21881420.17462551X-RAY DIFFRACTION100
4.2652-5.37280.19121450.16032542X-RAY DIFFRACTION100
5.3728-51.86170.26421520.20532617X-RAY DIFFRACTION100

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