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- PDB-6uf0: Crystal structure of N-(4-((4-methoxy-N-(2,2,2-trifluoroethyl)phe... -

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Basic information

Entry
Database: PDB / ID: 6uf0
TitleCrystal structure of N-(4-((4-methoxy-N-(2,2,2-trifluoroethyl)phenyl)sulfonamido)isoquinolin-1-yl)-N-((4-methoxyphenyl)sulfonyl)glycine bound to human Keap1 Kelch domain
ComponentsKelch-like ECH-associated protein 1
KeywordsPROTEIN BINDING / Protein-protein interaction inhibitor / Keap1 / Nrf2 activator
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 / ubiquitin-like ligase-substrate adaptor activity / transcription regulator inhibitor activity / inclusion body / cellular response to interleukin-4 / actin filament / centriolar satellite ...regulation of epidermal cell differentiation / Nuclear events mediated by NFE2L2 / 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 / KEAP1-NFE2L2 pathway / Antigen processing: Ubiquitination & Proteasome degradation / positive regulation of proteasomal ubiquitin-dependent protein catabolic process / Neddylation / midbody / cellular response to oxidative stress / ubiquitin-dependent protein catabolic process / RNA polymerase II-specific DNA-binding transcription factor binding / in utero embryonic development / proteasome-mediated ubiquitin-dependent protein catabolic process / Potential therapeutics for SARS / regulation of autophagy / Ub-specific processing proteases / protein ubiquitination / negative regulation of transcription by RNA polymerase II / endoplasmic reticulum / nucleoplasm / identical protein binding / cytosol / cytoplasm
Similarity search - Function
Kelch-type beta propeller / Kelch-like ECH-associated protein 1 / : / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / BTB-kelch protein / BTB/Kelch-associated / BTB And C-terminal Kelch / BTB And C-terminal Kelch / Kelch / Kelch motif ...Kelch-type beta propeller / Kelch-like ECH-associated protein 1 / : / KLHDC2/KLHL20/DRC7 Kelch-repeats domain / 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. / 6 Propeller / Neuraminidase / Broad-Complex, Tramtrack and Bric a brac / BTB/POZ domain / SKP1/BTB/POZ domain superfamily / Mainly Beta
Similarity search - Domain/homology
FORMIC ACID / Chem-Q5V / Chem-Q5Y / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.96 Å
AuthorsLazzara, P.R. / David, B.P. / Ankireddy, A. / Richardson, B.G. / Dye, K. / Ratia, K.M. / Reddy, S.P. / Moore, T.W.
Funding support United States, 2items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIH/NIAMS)1R01 AR069541-01A1 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)1R01 HL136946-01 United States
CitationJournal: J.Med.Chem. / Year: 2020
Title: Isoquinoline Kelch-like ECH-Associated Protein 1-Nuclear Factor (Erythroid-Derived 2)-like 2 (KEAP1-NRF2) Inhibitors with High Metabolic Stability.
Authors: Lazzara, P.R. / David, B.P. / Ankireddy, A. / Richardson, B.G. / Dye, K. / Ratia, K.M. / Reddy, S.P. / Moore, T.W.
History
DepositionSep 23, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Dec 18, 2019Provider: repository / Type: Initial release
Revision 1.1Jul 8, 2020Group: Database references / Category: citation / citation_author
Item: _citation.journal_volume / _citation.page_first ..._citation.journal_volume / _citation.page_first / _citation.page_last / _citation.year / _citation_author.identifier_ORCID
Revision 1.2Oct 11, 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 / pdbx_struct_conn_angle / struct_conn
Item: _database_2.pdbx_DOI / _database_2.pdbx_database_accession ..._database_2.pdbx_DOI / _database_2.pdbx_database_accession / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.value / _struct_conn.pdbx_dist_value / _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.ptnr1_label_seq_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

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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)64,93915
Polymers63,2512
Non-polymers1,68913
Water5,441302
1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,64210
Polymers31,6251
Non-polymers1,0179
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)32,2975
Polymers31,6251
Non-polymers6724
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)105.712, 57.350, 130.425
Angle α, β, γ (deg.)90.000, 107.530, 90.000
Int Tables number5
Space group name H-MI121

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Components

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Protein , 1 types, 2 molecules AB

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


Mass: 31625.381 Da / Num. of mol.: 2 / Fragment: UNP residues 321-609 / Mutation: E540A, E542A
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli BL21(DE3) (bacteria) / References: UniProt: Q14145

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Non-polymers , 6 types, 315 molecules

#2: Chemical ChemComp-Q5V / N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-methoxyphenyl)sulfonyl](2,2,2-trifluoroethyl)amino}isoquinolin-1-yl)glycine


Mass: 639.620 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C27H24F3N3O8S2 / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical
ChemComp-FMT / FORMIC ACID


Mass: 46.025 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: CH2O2
#4: Chemical ChemComp-DMS / DIMETHYL SULFOXIDE


Mass: 78.133 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C2H6OS / Comment: DMSO, precipitant*YM
#5: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 2 / Source method: obtained synthetically / Formula: Na
#6: Chemical ChemComp-Q5Y / N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-methoxyphenyl)sulfonyl]amino}naphthalen-1-yl)glycine


Mass: 556.607 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C26H24N2O8S2 / Feature type: SUBJECT OF INVESTIGATION
#7: Water ChemComp-HOH / water


Mass: 18.015 Da / Num. of mol.: 302 / Source method: isolated from a natural source / Formula: H2O

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Details

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: 2.98 Å3/Da / Density % sol: 58.73 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 3.1-3.8 M sodium formate, pH 7

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: APS / Beamline: 21-ID-F / Wavelength: 0.9787 Å
DetectorType: RAYONIX MX-300 / Detector: CCD / Date: Aug 16, 2019
RadiationMonochromator: diamond(111) / Protocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 0.9787 Å / Relative weight: 1
ReflectionResolution: 1.96→19.87 Å / Num. obs: 53571 / % possible obs: 99.7 % / Redundancy: 3.8 % / CC1/2: 0.998 / Rmerge(I) obs: 0.075 / Rpim(I) all: 0.045 / Rrim(I) all: 0.088 / Net I/σ(I): 10.5 / Num. measured all: 201576
Reflection shell

Diffraction-ID: 1

Resolution (Å)Redundancy (%)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.96-2.013.81.0121429837670.5460.6011.1791.499.9
8.98-19.873.40.02618945500.9980.0160.0334.190.9

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0238refinement
XDSdata reduction
Aimless0.7.4data scaling
MOLREPphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1U6D

1u6d


Resolution: 1.96→19.87 Å / Cor.coef. Fo:Fc: 0.97 / Cor.coef. Fo:Fc free: 0.957 / SU B: 4.034 / SU ML: 0.109 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.14 / ESU R Free: 0.136 / Stereochemistry target values: MAXIMUM LIKELIHOOD
Details: HYDROGENS HAVE BEEN ADDED IN THE RIDING POSITIONS U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2219 2818 5.3 %RANDOM
Rwork0.1793 ---
obs0.1815 50752 99.59 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å / Solvent model: MASK
Displacement parametersBiso max: 100.46 Å2 / Biso mean: 34.692 Å2 / Biso min: 17.18 Å2
Baniso -1Baniso -2Baniso -3
1--0.69 Å20 Å2-0.98 Å2
2--2.27 Å20 Å2
3----0.8 Å2
Refinement stepCycle: final / Resolution: 1.96→19.87 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4375 0 111 302 4788
Biso mean--56.23 40.52 -
Num. residues----570
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0110.0134591
X-RAY DIFFRACTIONr_bond_other_d0.0020.0174013
X-RAY DIFFRACTIONr_angle_refined_deg1.7161.6696250
X-RAY DIFFRACTIONr_angle_other_deg1.3881.5889225
X-RAY DIFFRACTIONr_dihedral_angle_1_deg8.1295569
X-RAY DIFFRACTIONr_dihedral_angle_2_deg30.00920.312256
X-RAY DIFFRACTIONr_dihedral_angle_3_deg14.99415655
X-RAY DIFFRACTIONr_dihedral_angle_4_deg20.4731544
X-RAY DIFFRACTIONr_chiral_restr0.0680.2559
X-RAY DIFFRACTIONr_gen_planes_refined0.0090.025330
X-RAY DIFFRACTIONr_gen_planes_other0.0010.021085
LS refinement shellResolution: 1.96→2.011 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.318 207 -
Rwork0.297 3744 -
all-3951 -
obs--99.85 %

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