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- PDB-9f2q: Crystal structure of Keap1 kelch domain in complex with a tetrahy... -

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Basic information

Entry
Database: PDB / ID: 9f2q
TitleCrystal structure of Keap1 kelch domain in complex with a tetrahydroisoquinoline-based small molecule inhibitor at 1.2A resolution
ComponentsKelch-like ECH-associated protein 1
KeywordsPEPTIDE BINDING PROTEIN / Keap1 / Nrf2 / Oxidative stress / Inhibitor
Function / homology
Function and homology information


regulation of epidermal cell differentiation / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body ...regulation of epidermal cell differentiation / Neddylation / Ub-specific processing proteases / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / negative regulation of response to oxidative stress / Cul3-RING ubiquitin ligase complex / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body / cellular response to interleukin-4 / actin filament / centriolar satellite / disordered domain specific binding / cellular response to oxidative stress / ubiquitin-dependent protein catabolic process / midbody / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / regulation of autophagy / protein ubiquitination / regulation of DNA-templated transcription / endoplasmic reticulum / negative regulation of transcription by RNA polymerase II / protein-containing complex / nucleoplasm / identical protein binding / cytoplasm / cytosol
Similarity search - Function
Kelch-like ECH-associated protein 1 / : / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch motif / Kelch / 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 motif / Kelch / Kelch repeat type 1 / Kelch-type beta propeller / BTB/POZ domain / BTB domain profile. / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily
Similarity search - Domain/homology
: / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesMus musculus (house mouse)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / Resolution: 1.2 Å
AuthorsNarayanan, D. / Bach, A. / Gajhede, M.
Funding support Denmark, 1items
OrganizationGrant numberCountry
LundbeckfondenR366-2021-270 Denmark
Citation
Journal: J.Med.Chem. / Year: 2024
Title: Structure-Guided Conformational Restriction Leading to High-Affinity, Selective, and Cell-Active Tetrahydroisoquinoline-Based Noncovalent Keap1-Nrf2 Inhibitors.
Authors: Qin, Y. / Poulsen, C. / Narayanan, D. / Chan, C.B. / Chen, X. / Montes, B.R. / Tran, K.T. / Mukminova, E. / Lin, C. / Gajhede, M. / Bullock, A.N. / Olagnier, D. / Bach, A.
#1: Journal: J Med Chem / Year: 2022
Title: Development of Noncovalent Small-Molecule Keap1-Nrf2 Inhibitors by Fragment-Based Drug Discovery.
Authors: Narayanan, D. / Tran, K.T. / Pallesen, J.S. / Solbak, S.M.O. / Qin, Y. / Mukminova, E. / Luchini, M. / Vasilyeva, K.O. / Gonzalez Chichon, D. / Goutsiou, G. / Poulsen, C. / Haapanen, N. / ...Authors: Narayanan, D. / Tran, K.T. / Pallesen, J.S. / Solbak, S.M.O. / Qin, Y. / Mukminova, E. / Luchini, M. / Vasilyeva, K.O. / Gonzalez Chichon, D. / Goutsiou, G. / Poulsen, C. / Haapanen, N. / Popowicz, G.M. / Sattler, M. / Olagnier, D. / Gajhede, M. / Bach, A.
History
DepositionApr 23, 2024Deposition site: PDBE / Processing site: PDBE
Revision 1.0Oct 30, 2024Provider: repository / Type: Initial release
Revision 1.1Nov 27, 2024Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation_author.identifier_ORCID

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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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)35,62524
Polymers33,3621
Non-polymers2,26323
Water6,287349
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: gel filtration, Monomer
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Buried area3610 Å2
ΔGint-75 kcal/mol
Surface area12640 Å2
MethodPISA
Unit cell
Length a, b, c (Å)103.136, 103.136, 55.206
Angle α, β, γ (deg.)90.00, 90.00, 120.00
Int Tables number169
Space group name H-MP61

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Components

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Protein , 1 types, 1 molecules A

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


Mass: 33362.297 Da / Num. of mol.: 1
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Mus musculus (house mouse) / Gene: Keap1, Inrf2, Kiaa0132
Production host: Escherichia coli 'BL21-Gold(DE3)pLysS AG' (bacteria)
References: UniProt: Q9Z2X8

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Non-polymers , 5 types, 372 molecules

#2: Chemical ChemComp-A1H9B / (R)-2-(2-((4-methoxyphenyl)sulfonyl)-1,2,3,4-tetrahydroisoquinolin-7-yl)-2-(9-oxo-9H-fluorene-4-carboxamido)acetate / (2~{R})-2-[2-(4-methoxyphenyl)sulfonyl-3,4-dihydro-1~{H}-isoquinolin-7-yl]-2-[(9-oxidanylidenefluoren-4-yl)carbonylamino]ethanoic acid


Mass: 582.623 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C32H26N2O7S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-SO4 / SULFATE ION


Mass: 96.063 Da / Num. of mol.: 5 / Source method: obtained synthetically / Formula: SO4
#4: Chemical
ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 14 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-CL / CHLORIDE ION


Mass: 35.453 Da / Num. of mol.: 3 / Source method: obtained synthetically / Formula: Cl
#6: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 349 / Source method: isolated from a natural source / Formula: H2O

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Details

Has ligand of interestY
Has protein modificationN

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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: 2.67 Å3/Da / Density % sol: 53.89 %
Crystal growTemperature: 293 K / Method: vapor diffusion, hanging drop / pH: 5.6
Details: 0.5 M AMMONIUM SULFATE, 0.1 M SODIUM CITRATE TRIBASIC DIHYDRATE PH 5.6 AND 1.0 M LITHIUM SULFATE MONOHYDRATE

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: MAX IV / Beamline: BioMAX / Wavelength: 0.9762 Å
DetectorType: DECTRIS EIGER X 16M / Detector: PIXEL / Date: Apr 23, 2022
RadiationMonochromator: Si (111), double crystal monochromator / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9762 Å / Relative weight: 1
ReflectionResolution: 1.2→46.96 Å / Num. obs: 104131 / % possible obs: 99.9 % / Redundancy: 9.5 % / Biso Wilson estimate: 12.25 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.067 / Rpim(I) all: 0.022 / Rrim(I) all: 0.071 / Χ2: 1.02 / Net I/σ(I): 15.6
Reflection shellResolution: 1.2→1.22 Å / % possible obs: 98.1 % / Redundancy: 5.1 % / Rmerge(I) obs: 0.743 / Num. measured all: 25298 / Num. unique obs: 5001 / CC1/2: 0.713 / Rpim(I) all: 0.369 / Rrim(I) all: 0.835 / Χ2: 1.13 / Net I/σ(I) obs: 2.3

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Processing

Software
NameVersionClassification
XDSdata reduction
Aimlessdata scaling
PHASERphasing
PHENIX(1.20.1_4487: ???)refinement
RefinementMethod to determine structure: MOLECULAR REPLACEMENT / Resolution: 1.2→44.66 Å / SU ML: 0.1 / Cross valid method: FREE R-VALUE / σ(F): 0.35 / Phase error: 14.05 / Stereochemistry target values: ML
RfactorNum. reflection% reflection
Rfree0.143 4995 4.8 %
Rwork0.1242 --
obs0.1251 104057 99.85 %
Solvent computationShrinkage radii: 0.9 Å / VDW probe radii: 1.1 Å / Solvent model: FLAT BULK SOLVENT MODEL
Refinement stepCycle: LAST / Resolution: 1.2→44.66 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms2235 0 126 349 2710
Refine LS restraints
Refine-IDTypeDev idealNumber
X-RAY DIFFRACTIONf_bond_d0.0072582
X-RAY DIFFRACTIONf_angle_d1.0453543
X-RAY DIFFRACTIONf_dihedral_angle_d6.816400
X-RAY DIFFRACTIONf_chiral_restr0.094358
X-RAY DIFFRACTIONf_plane_restr0.009467
LS refinement shell
Resolution (Å)Rfactor RfreeNum. reflection RfreeRfactor RworkNum. reflection RworkRefine-ID% reflection obs (%)
1.2-1.210.23371780.19783139X-RAY DIFFRACTION97
1.21-1.230.19571600.18513292X-RAY DIFFRACTION99
1.23-1.240.22371490.16743305X-RAY DIFFRACTION100
1.24-1.260.23641650.16693305X-RAY DIFFRACTION100
1.26-1.280.16581680.15923262X-RAY DIFFRACTION100
1.28-1.290.16241630.14633275X-RAY DIFFRACTION100
1.29-1.310.17071520.13853314X-RAY DIFFRACTION100
1.31-1.330.17991840.13543275X-RAY DIFFRACTION100
1.33-1.350.15861640.1333307X-RAY DIFFRACTION100
1.35-1.370.15791680.12133298X-RAY DIFFRACTION100
1.37-1.40.13751580.12033268X-RAY DIFFRACTION100
1.4-1.420.15171590.11893302X-RAY DIFFRACTION100
1.42-1.450.14031970.11613297X-RAY DIFFRACTION100
1.45-1.480.13341850.11293288X-RAY DIFFRACTION100
1.48-1.510.12871640.11753290X-RAY DIFFRACTION100
1.51-1.550.14151640.10673287X-RAY DIFFRACTION100
1.55-1.590.13331550.10543318X-RAY DIFFRACTION100
1.59-1.630.13661910.10763292X-RAY DIFFRACTION100
1.63-1.680.14771730.10763279X-RAY DIFFRACTION100
1.68-1.730.14121490.10723329X-RAY DIFFRACTION100
1.73-1.790.12761510.10953318X-RAY DIFFRACTION100
1.79-1.870.13151420.11173326X-RAY DIFFRACTION100
1.87-1.950.14411620.11313342X-RAY DIFFRACTION100
1.95-2.050.111480.10593350X-RAY DIFFRACTION100
2.05-2.180.12751700.10713283X-RAY DIFFRACTION100
2.18-2.350.11761570.11133342X-RAY DIFFRACTION100
2.35-2.590.12741730.12443319X-RAY DIFFRACTION100
2.59-2.960.14661700.1263336X-RAY DIFFRACTION100
2.96-3.730.12881720.12673341X-RAY DIFFRACTION100
3.73-44.660.16282040.14493383X-RAY DIFFRACTION100

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