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- PDB-6v6z: Crystal structure of N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-meth... -

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Basic information

Entry
Database: PDB / ID: 6v6z
TitleCrystal structure of N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-methoxyphenyl)sulfonyl]amino}naphthalen-1-yl)glycine bound to human Keap1 Kelch domain
ComponentsKelch-like ECH-associated protein 1
KeywordsPROTEIN BINDING/INHIBITOR / Protein-protein interaction inhibitor / Keap1 / Nrf2 activator / Protein binding-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
DITHIANE DIOL / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / FORMIC ACID / Chem-Q5Y / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 1.6 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: Acs Med.Chem.Lett. / Year: 2020
Title: Synthesis and Evaluation of Noncovalent Naphthalene-Based KEAP1-NRF2 Inhibitors.
Authors: Lazzara, P.R. / Jain, A.D. / Maldonado, A.C. / Richardson, B. / Skowron, K.J. / David, B.P. / Siddiqui, Z. / Ratia, K.M. / Moore, T.W.
History
DepositionDec 6, 2019Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 29, 2020Provider: repository / Type: Initial release
Revision 1.1Apr 7, 2021Group: Derived calculations / Structure summary / Category: pdbx_struct_conn_angle / struct / struct_conn
Item: _pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id ..._pdbx_struct_conn_angle.ptnr1_auth_asym_id / _pdbx_struct_conn_angle.ptnr1_auth_comp_id / _pdbx_struct_conn_angle.ptnr1_auth_seq_id / _pdbx_struct_conn_angle.ptnr1_label_asym_id / _pdbx_struct_conn_angle.ptnr1_label_atom_id / _pdbx_struct_conn_angle.ptnr1_label_comp_id / _pdbx_struct_conn_angle.ptnr1_label_seq_id / _pdbx_struct_conn_angle.ptnr2_auth_asym_id / _pdbx_struct_conn_angle.ptnr2_auth_seq_id / _pdbx_struct_conn_angle.ptnr2_label_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_asym_id / _pdbx_struct_conn_angle.ptnr3_auth_comp_id / _pdbx_struct_conn_angle.ptnr3_auth_seq_id / _pdbx_struct_conn_angle.ptnr3_label_asym_id / _pdbx_struct_conn_angle.ptnr3_label_atom_id / _pdbx_struct_conn_angle.ptnr3_label_comp_id / _pdbx_struct_conn_angle.ptnr3_label_seq_id / _pdbx_struct_conn_angle.value / _struct.title / _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 / _struct_conn.ptnr2_symmetry
Revision 1.2Oct 11, 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

Downloads & links

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Assembly

Deposited unit
A: Kelch-like ECH-associated protein 1
B: Kelch-like ECH-associated protein 1
C: Kelch-like ECH-associated protein 1
D: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)132,02679
Polymers126,5024
Non-polymers5,52475
Water18,8621047
1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,75716
Polymers31,6251
Non-polymers1,13215
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)33,05622
Polymers31,6251
Non-polymers1,43121
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
3
C: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,14021
Polymers31,6251
Non-polymers1,51420
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
4
D: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)33,07320
Polymers31,6251
Non-polymers1,44719
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
Unit cell
Length a, b, c (Å)59.360, 75.543, 97.947
Angle α, β, γ (deg.)74.550, 77.540, 67.480
Int Tables number1
Space group name H-MP1

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Components

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Protein , 1 types, 4 molecules ABCD

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


Mass: 31625.381 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Homo sapiens (human) / Gene: KEAP1, INRF2, KIAA0132, KLHL19 / Production host: Escherichia coli (E. coli) / References: UniProt: Q14145

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Non-polymers , 6 types, 1122 molecules

#2: Chemical...
ChemComp-FMT / FORMIC ACID / Formic acid


Mass: 46.025 Da / Num. of mol.: 61 / Source method: obtained synthetically / Formula: CH2O2
#3: Chemical
ChemComp-Q5Y / N-[(4-methoxyphenyl)sulfonyl]-N-(4-{[(4-methoxyphenyl)sulfonyl]amino}naphthalen-1-yl)glycine


Mass: 556.607 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C26H24N2O8S2 / Feature type: SUBJECT OF INVESTIGATION
#4: Chemical
ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 8 / Source method: obtained synthetically / Formula: Na
#5: Chemical ChemComp-DTD / DITHIANE DIOL


Mass: 152.235 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H8O2S2
#6: Chemical ChemComp-DTT / 2,3-DIHYDROXY-1,4-DITHIOBUTANE / 1,4-DITHIOTHREITOL / Dithiothreitol


Mass: 154.251 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C4H10O2S2
#7: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 1047 / 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: 3.07 Å3/Da / Density % sol: 59.92 %
Crystal growTemperature: 289 K / Method: vapor diffusion, hanging drop / pH: 7 / Details: 3.5-3.8 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: Jun 22, 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: 1.6→19.74 Å / Num. obs: 182432 / % possible obs: 92 % / Redundancy: 2 % / CC1/2: 0.999 / Rmerge(I) obs: 0.033 / Rpim(I) all: 0.033 / Rrim(I) all: 0.047 / Net I/σ(I): 10.5
Reflection shell

Diffraction-ID: 1 / Redundancy: 2 %

Resolution (Å)Rmerge(I) obsNum. measured allNum. unique obsCC1/2Rpim(I) allRrim(I) allNet I/σ(I) obs% possible all
1.6-1.630.4631845892490.6650.4630.6541.694.3
8.76-19.730.017197010070.9980.0170.02426.683.2

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
REFMAC5.8.0238refinement
HKL-2000data reduction
SCALEPACKdata scaling
MOLREPphasing
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: PDB entry 1U6D

1u6d


Resolution: 1.6→19.73 Å / Cor.coef. Fo:Fc: 0.961 / Cor.coef. Fo:Fc free: 0.956 / SU B: 1.823 / SU ML: 0.061 / Cross valid method: THROUGHOUT / σ(F): 0 / ESU R: 0.089 / ESU R Free: 0.086
Details: HYDROGENS HAVE BEEN USED IF PRESENT IN THE INPUT U VALUES : REFINED INDIVIDUALLY
RfactorNum. reflection% reflectionSelection details
Rfree0.2104 9206 5 %RANDOM
Rwork0.1918 ---
obs0.1927 173224 91.99 %-
Solvent computationIon probe radii: 0.8 Å / Shrinkage radii: 0.8 Å / VDW probe radii: 1.2 Å
Displacement parametersBiso max: 69.34 Å2 / Biso mean: 23.41 Å2 / Biso min: 10.74 Å2
Baniso -1Baniso -2Baniso -3
1-1.36 Å20.11 Å2-0.52 Å2
2---0.77 Å20.37 Å2
3----0.21 Å2
Refinement stepCycle: final / Resolution: 1.6→19.73 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms8747 0 359 1047 10153
Biso mean--32.39 32.31 -
Num. residues----1141
Refine LS restraints
Refine-IDTypeDev idealDev ideal targetNumber
X-RAY DIFFRACTIONr_bond_refined_d0.0060.0129330
X-RAY DIFFRACTIONr_angle_refined_deg1.441.66312632
X-RAY DIFFRACTIONr_dihedral_angle_1_deg7.59351159
X-RAY DIFFRACTIONr_dihedral_angle_2_deg29.62820.31516
X-RAY DIFFRACTIONr_dihedral_angle_3_deg11.717151334
X-RAY DIFFRACTIONr_dihedral_angle_4_deg18.1541589
X-RAY DIFFRACTIONr_chiral_restr0.0980.21132
X-RAY DIFFRACTIONr_gen_planes_refined0.0080.027382
LS refinement shellResolution: 1.6→1.642 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.326 718 -
Rwork0.307 13172 -
all-13890 -
obs--94.45 %

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