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

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Basic information

Entry
Database: PDB / ID: 5wiy
TitleKelch domain of human Keap1 bound to small molecule inhibitor fragment: 4-amino-1,7-dihydro-6H-pyrazolo[3,4-d]pyrimidine-6-thione
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 / 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-1XM / 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 20, 2017Deposition site: RCSB / Processing site: RCSB
Revision 1.0Sep 26, 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
A: Kelch-like ECH-associated protein 1
B: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)74,2546
Polymers73,7982
Non-polymers4554
Water73941
1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)37,3555
Polymers36,8991
Non-polymers4554
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Kelch-like ECH-associated protein 1


Theoretical massNumber of molelcules
Total (without water)36,8991
Polymers36,8991
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)162.040, 69.180, 78.600
Angle α, β, γ (deg.)90.00, 117.83, 90.00
Int Tables number5
Space group name H-MC121

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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, C613S
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 / Sulfate


Mass: 96.063 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: SO4
#3: Chemical ChemComp-1XM / 4-amino-1,7-dihydro-6H-pyrazolo[3,4-d]pyrimidine-6-thione


Mass: 167.192 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C5H5N5S / Feature type: SUBJECT OF INVESTIGATION
#4: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 41 / 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: 2.64 Å3/Da / Density % sol: 53.4 %
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 / Ambient temp details: Nitrogen stream
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→51.93 Å / Num. obs: 37651 / % possible obs: 99.41 % / Redundancy: 8.7 % / CC1/2: 0.909 / Rmerge(I) obs: 0.8581 / Net I/σ(I): 28.5
Reflection shellResolution: 2.23→2.31 Å / Redundancy: 8.2 % / Rmerge(I) obs: 2.115 / Mean I/σ(I) obs: 2.46 / Num. unique obs: 3724 / CC1/2: 0.225 / % possible all: 98.37

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Processing

Software
NameVersionClassification
PHENIX(1.12_2829: ???)refinement
XDSdata reduction
XDSdata scaling
PHASERphasing
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 5WFL

5wfl


Resolution: 2.23→51.926 Å / SU ML: 0.32 / Cross valid method: FREE R-VALUE / σ(F): 1.34 / Phase error: 25.42 / Stereochemistry target values: ML
RfactorNum. reflection% reflectionSelection details
Rfree0.2387 1990 5.31 %Random selection
Rwork0.1961 ---
obs0.1983 37445 99.42 %-
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.11 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 2.23→51.926 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4396 0 26 41 4463
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0074527
X-RAY DIFFRACTIONf_angle_d0.9346168
X-RAY DIFFRACTIONf_dihedral_angle_d10.9192605
X-RAY DIFFRACTIONf_chiral_restr0.06656
X-RAY DIFFRACTIONf_plane_restr0.006810
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
2.2301-2.28590.34171360.32382476X-RAY DIFFRACTION98
2.2859-2.34770.33571420.28932505X-RAY DIFFRACTION99
2.3477-2.41670.30071390.27872510X-RAY DIFFRACTION99
2.4167-2.49470.3121440.28352521X-RAY DIFFRACTION99
2.4947-2.58390.30261290.26212509X-RAY DIFFRACTION99
2.5839-2.68740.29811510.24432546X-RAY DIFFRACTION100
2.6874-2.80970.29871390.22492538X-RAY DIFFRACTION99
2.8097-2.95780.24281370.21392509X-RAY DIFFRACTION100
2.9578-3.14310.29431470.21742544X-RAY DIFFRACTION99
3.1431-3.38570.23651400.19572528X-RAY DIFFRACTION100
3.3857-3.72630.19621490.18032534X-RAY DIFFRACTION100
3.7263-4.26530.20081420.1472564X-RAY DIFFRACTION100
4.2653-5.3730.16431440.1312536X-RAY DIFFRACTION99
5.373-51.93970.24131510.18542635X-RAY DIFFRACTION100
Refinement TLS params.

Method: refined / 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)Origin x (Å)Origin y (Å)Origin z (Å)
10.3720.16620.68351.19130.96311.9423-0.0149-1.71081.48550.10210.2185-0.5898-0.41230.9944-0.40140.4287-0.1429-0.09211.4419-0.59680.7104449.471976.2782126.5742
20.7751-0.24981.6122.14-0.17063.5162-0.3752-2.3706-0.28160.54210.6845-0.60760.48180.5626-0.27010.37070.1542-0.09011.16430.02220.5362447.761764.7039126.6357
31.38030.72050.6683.3304-0.43291.1425-0.5643-1.6559-0.30650.20280.1616-0.45970.54530.67150.1740.38180.2879-0.02031.1874-0.02580.5197449.987262.6762122.1354
45.6476-1.6333-2.45234.1070.49682.0361-0.9039-1.2438-1.15070.57010.29-0.23220.66420.48790.32430.44860.17890.11410.58640.18880.5454431.199458.4133126.1208
54.199-0.0419-1.77322.74031.01161.79180.4675-1.09081.11060.27080.1364-0.2263-0.62420.7765-0.33040.459-0.10750.03540.6535-0.26760.5523430.795379.1762127.8544
62.1308-1.57390.2486.9153.84352.8910.1256-2.33991.0834-0.9580.4135-1.0029-0.63820.9257-0.06980.2322-0.0598-0.0721.0505-0.36810.6555445.375375.32125.2771
75.5867-4.2228-2.29598.60694.07223.31250.1128-0.0362-0.13680.0864-0.155-0.14230.03830.01710.04230.2411-0.0274-0.04610.19340.04490.272435.118760.5335175.189
83.533-1.07260.56483.35270.4411.5557-0.0037-0.22330.22020.2064-0.0557-0.1799-0.06830.00030.0580.2684-0.0197-0.00020.1799-0.01810.2714433.096474.4076172.8618
95.2259-0.01190.93353.84830.5521.52610.03360.4360.2678-0.3753-0.0857-0.0854-0.18190.04070.04330.29380.0108-0.00150.25620.0040.1906425.605377.2684159.5462
107.24752.0084-1.51173.95160.33290.5574-0.1550.8636-0.064-0.53260.2248-0.0965-0.2312-0.4461-0.07840.32170.0401-0.05730.2553-0.02290.2079416.319873.8291155.0406
113.87420.06061.90614.01980.34044.13710.10870.4924-0.4976-0.6511-0.02870.16510.1718-0.027-0.05540.3330.0271-0.06330.2388-0.07130.2892417.030459.4915158.0509
126.63670.7350.70846.10841.88645.0970.3782-0.2056-0.54-0.3561-0.17230.04490.4990.0672-0.14940.31230.0223-0.07510.1664-0.02680.2461425.741855.087165.632
130.9917-0.8363-0.26153.4519-0.17872.33840.11640.0858-0.292-0.1693-0.15680.08070.21090.00990.05250.23870.0322-0.0250.19510.00290.3264428.242255.3065170.2272
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection details
1X-RAY DIFFRACTION1chain 'A' and (resid 326 through 354 )
2X-RAY DIFFRACTION2chain 'A' and (resid 355 through 377 )
3X-RAY DIFFRACTION3chain 'A' and (resid 378 through 406 )
4X-RAY DIFFRACTION4chain 'A' and (resid 407 through 499 )
5X-RAY DIFFRACTION5chain 'A' and (resid 500 through 596 )
6X-RAY DIFFRACTION6chain 'A' and (resid 597 through 609 )
7X-RAY DIFFRACTION7chain 'B' and (resid 325 through 354 )
8X-RAY DIFFRACTION8chain 'B' and (resid 355 through 416 )
9X-RAY DIFFRACTION9chain 'B' and (resid 417 through 475 )
10X-RAY DIFFRACTION10chain 'B' and (resid 476 through 500 )
11X-RAY DIFFRACTION11chain 'B' and (resid 501 through 547 )
12X-RAY DIFFRACTION12chain 'B' and (resid 548 through 569 )
13X-RAY DIFFRACTION13chain 'B' and (resid 570 through 613 )

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