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- PDB-6z6a: Keap1 macrocycle complex -

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Basic information

Entry
Database: PDB / ID: 6z6a
TitleKeap1 macrocycle complex
ComponentsKelch-like ECH-associated protein 1
KeywordsLIGASE / macrocycle / 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-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 / SKP1/BTB/POZ domain superfamily
Similarity search - Domain/homology
Chem-Q9E / Kelch-like ECH-associated protein 1
Similarity search - Component
Biological speciesHomo sapiens (human)
MethodX-RAY DIFFRACTION / SYNCHROTRON / MOLECULAR REPLACEMENT / molecular replacement / Resolution: 2.37 Å
AuthorsJohansson, P.
CitationJournal: J.Med.Chem. / Year: 2021
Title: Mining Natural Products for Macrocycles to Drug Difficult Targets.
Authors: Begnini, F. / Poongavanam, V. / Over, B. / Castaldo, M. / Geschwindner, S. / Johansson, P. / Tyagi, M. / Tyrchan, C. / Wissler, L. / Sjo, P. / Schiesser, S. / Kihlberg, J.
History
DepositionMay 28, 2020Deposition site: PDBE / Processing site: PDBE
Revision 1.0Dec 30, 2020Provider: repository / Type: Initial release
Revision 1.1Feb 10, 2021Group: 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 2.0Feb 17, 2021Group: Derived calculations / Non-polymer description ...Derived calculations / Non-polymer description / Source and taxonomy / Structure summary
Category: chem_comp / entity ...chem_comp / entity / entity_src_gen / pdbx_entity_nonpoly
Item: _chem_comp.formula / _chem_comp.formula_weight ..._chem_comp.formula / _chem_comp.formula_weight / _chem_comp.name / _chem_comp.pdbx_synonyms / _entity.formula_weight / _entity.pdbx_description / _entity_src_gen.pdbx_host_org_ncbi_taxonomy_id / _entity_src_gen.pdbx_host_org_scientific_name / _pdbx_entity_nonpoly.name
Revision 2.1Jan 24, 2024Group: 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
hetero molecules


Theoretical massNumber of molelcules
Total (without water)64,6795
Polymers64,1302
Non-polymers5493
Water3,279182
1
A: Kelch-like ECH-associated protein 1
hetero molecules


Theoretical massNumber of molelcules
Total (without water)32,6144
Polymers32,0651
Non-polymers5493
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
2
B: Kelch-like ECH-associated protein 1


Theoretical massNumber of molelcules
Total (without water)32,0651
Polymers32,0651
Non-polymers00
Water181
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1
MethodPISA
Unit cell
Length a, b, c (Å)75.650, 75.800, 203.130
Angle α, β, γ (deg.)90.000, 90.000, 90.000
Int Tables number19
Space group name H-MP212121

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Components

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


Mass: 32064.867 Da / Num. of mol.: 2
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
#2: Chemical ChemComp-Q9E / (5S,8R)-8-[[(2S)-1-ethanoylpyrrolidin-2-yl]carbonylamino]-N,N-dimethyl-7,11-bis(oxidanylidene)-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-5-carboxamide / (5~{S},8~{R})-8-[[(2~{S})-1-ethanoyl-2,3-dihydropyrrol-2-yl]carbonylamino]-~{N},~{N}-dimethyl-7,11-bis(oxidanylidene)-10-oxa-3-thia-6-azabicyclo[10.4.0]hexadeca-1(16),12,14-triene-5-carboxamide


Mass: 490.573 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: C23H30N4O6S / Feature type: SUBJECT OF INVESTIGATION
#3: Chemical ChemComp-NA / SODIUM ION


Mass: 22.990 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Na
#4: Chemical ChemComp-CL / CHLORIDE ION / Chloride


Mass: 35.453 Da / Num. of mol.: 1 / Source method: obtained synthetically / Formula: Cl
#5: Water ChemComp-HOH / water / Water


Mass: 18.015 Da / Num. of mol.: 182 / Source method: isolated from a natural source / Formula: H2O
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: 4.54 Å3/Da / Density % sol: 72.91 %
Crystal growTemperature: 293 K / Method: vapor diffusion, sitting drop
Details: 200 nL of protein (11-13 mg / mL) and 200 nL of well solution (3.7 to 4.1 M ammonium acetate, 0.09 M sodium acetate pH 4.6 and 10 mM cadmium chloride).

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Data collection

DiffractionMean temperature: 100 K / Serial crystal experiment: N
Diffraction sourceSource: SYNCHROTRON / Site: ESRF / Beamline: ID29 / Wavelength: 1.07227 Å
DetectorType: DECTRIS PILATUS3 6M / Detector: PIXEL / Date: Feb 23, 2018
RadiationProtocol: SINGLE WAVELENGTH / Monochromatic (M) / Laue (L): M / Scattering type: x-ray
Radiation wavelengthWavelength: 1.07227 Å / Relative weight: 1
ReflectionResolution: 2.37→47.37 Å / Num. obs: 48272 / % possible obs: 99.9 % / Redundancy: 6.5 % / Biso Wilson estimate: 80.94 Å2 / CC1/2: 0.999 / Rmerge(I) obs: 0.077 / Rpim(I) all: 0.033 / Rrim(I) all: 0.084 / Net I/σ(I): 15.4 / Num. measured all: 312117 / Scaling rejects: 43
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
2.37-2.456.21.492904146620.5270.6481.6281.399.9
9.18-47.3760.02757209480.9990.0120.0341.799

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Phasing

PhasingMethod: molecular replacement

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Processing

Software
NameVersionClassificationNB
XDSdata reduction
Aimless0.6.2data scaling
PHASERphasing
BUSTER2.11.7refinement
PDB_EXTRACT3.25data extraction
RefinementMethod to determine structure: MOLECULAR REPLACEMENT
Starting model: 1ZGK

1zgk


Resolution: 2.37→47.37 Å / Cor.coef. Fo:Fc: 0.949 / Cor.coef. Fo:Fc free: 0.934 / SU R Cruickshank DPI: 0.178 / Cross valid method: THROUGHOUT / σ(F): 0 / SU R Blow DPI: 0.18 / SU Rfree Blow DPI: 0.153 / SU Rfree Cruickshank DPI: 0.153
RfactorNum. reflection% reflectionSelection details
Rfree0.209 2356 4.89 %RANDOM
Rwork0.192 ---
obs0.193 48155 99.7 %-
Displacement parametersBiso max: 151.36 Å2 / Biso mean: 70 Å2 / Biso min: 46.76 Å2
Baniso -1Baniso -2Baniso -3
1-6.4853 Å20 Å20 Å2
2---5.2305 Å20 Å2
3----1.2548 Å2
Refine analyzeLuzzati coordinate error obs: 0.32 Å
Refinement stepCycle: final / Resolution: 2.37→47.37 Å
ProteinNucleic acidLigandSolventTotal
Num. atoms4372 0 36 182 4590
Biso mean--77.88 67.98 -
Num. residues----570
Refine LS restraints
Refine-IDTypeNumberRestraint functionWeightDev ideal
X-RAY DIFFRACTIONt_dihedral_angle_d1484SINUSOIDAL2
X-RAY DIFFRACTIONt_trig_c_planes
X-RAY DIFFRACTIONt_gen_planes791HARMONIC5
X-RAY DIFFRACTIONt_it4515HARMONIC20
X-RAY DIFFRACTIONt_nbd0SEMIHARMONIC5
X-RAY DIFFRACTIONt_improper_torsion
X-RAY DIFFRACTIONt_pseud_angle
X-RAY DIFFRACTIONt_chiral_improper_torsion561SEMIHARMONIC5
X-RAY DIFFRACTIONt_sum_occupancies
X-RAY DIFFRACTIONt_utility_distance
X-RAY DIFFRACTIONt_utility_angle
X-RAY DIFFRACTIONt_utility_torsion
X-RAY DIFFRACTIONt_ideal_dist_contact5011SEMIHARMONIC4
X-RAY DIFFRACTIONt_bond_d4515HARMONIC20.01
X-RAY DIFFRACTIONt_angle_deg6152HARMONIC21.16
X-RAY DIFFRACTIONt_omega_torsion3.87
X-RAY DIFFRACTIONt_other_torsion17.35
LS refinement shellResolution: 2.37→2.43 Å / Rfactor Rfree error: 0 / Total num. of bins used: 20
RfactorNum. reflection% reflection
Rfree0.2497 189 5.47 %
Rwork0.2331 3269 -
all0.234 3458 -
obs--98.67 %
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)
13.05710.7584-0.2371.35790.0050.9158-0.07280.29310.154-0.05940.10630.0329-0.1486-0.1095-0.0335-0.3689-0.0110.0312-0.2459-0.0737-0.3392-28.773622.3809-11.8883
21.79371.20670.5732.43480.53441.76420.2163-0.22120.00330.1635-0.2927-0.06120.1173-0.02270.0764-0.3041-0.04930.1334-0.3744-0.037-0.327-2.98329.1302-38.7674
Refinement TLS group
IDRefine-IDRefine TLS-IDSelection detailsAuth asym-IDAuth seq-ID
1X-RAY DIFFRACTION1{ A|* }A325 - 609
2X-RAY DIFFRACTION2{ B|* }B325 - 609

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