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- PDB-9c0b: E.coli GroEL + PBZ1587 inhibitor -

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Basic information

Entry
Database: PDB / ID: 9c0b
TitleE.coli GroEL + PBZ1587 inhibitor
Components60 kDa chaperonin
KeywordsCHAPERONE / GroEL / Inhibitor
Function / homology
Function and homology information


GroEL-GroES complex / chaperonin ATPase / mitochondrial unfolded protein response / protein import into mitochondrial intermembrane space / chaperone cofactor-dependent protein refolding / positive regulation of interferon-alpha production / isomerase activity / ATP-dependent protein folding chaperone / positive regulation of interleukin-6 production / positive regulation of type II interferon production ...GroEL-GroES complex / chaperonin ATPase / mitochondrial unfolded protein response / protein import into mitochondrial intermembrane space / chaperone cofactor-dependent protein refolding / positive regulation of interferon-alpha production / isomerase activity / ATP-dependent protein folding chaperone / positive regulation of interleukin-6 production / positive regulation of type II interferon production / unfolded protein binding / positive regulation of T cell activation / protein-folding chaperone binding / response to heat / protein refolding / ATP binding / metal ion binding
Similarity search - Function
Chaperonin Cpn60, conserved site / Chaperonins cpn60 signature. / Chaperonin Cpn60/GroEL / GroEL-like equatorial domain superfamily / TCP-1-like chaperonin intermediate domain superfamily / GroEL-like apical domain superfamily / TCP-1/cpn60 chaperonin family / Chaperonin Cpn60/GroEL/TCP-1 family
Similarity search - Domain/homology
: / Chaperonin GroEL
Similarity search - Component
Biological speciesEscherichia coli (E. coli)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.26 Å
AuthorsWatson, E.R. / Lander, G.C.
Funding support United States, 3items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)NS095892 United States
National Institutes of Health/National Heart, Lung, and Blood Institute (NIH/NHLBI)S10OD021634 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)GM120350 United States
CitationJournal: J Am Chem Soc / Year: 2024
Title: Bis-sulfonamido-2-phenylbenzoxazoles Validate the GroES/EL Chaperone System as a Viable Antibiotic Target.
Authors: Jack Godek / Jared Sivinski / Edmond R Watson / Felicidad Lebario / Wenli Xu / Mckayla Stevens / Christopher J Zerio / Andrew J Ambrose / Xiaoyi Zhu / Carlee A Trindl / Donna D Zhang / ...Authors: Jack Godek / Jared Sivinski / Edmond R Watson / Felicidad Lebario / Wenli Xu / Mckayla Stevens / Christopher J Zerio / Andrew J Ambrose / Xiaoyi Zhu / Carlee A Trindl / Donna D Zhang / Steven M Johnson / Gabriel C Lander / Eli Chapman /
Abstract: We recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential antibiotics against and the ESKAPE pathogens but were unable to establish GroES/GroEL as the ...We recently reported on small-molecule inhibitors of the GroES/GroEL chaperone system as potential antibiotics against and the ESKAPE pathogens but were unable to establish GroES/GroEL as the cellular target, leading to cell death. In this study, using two of our most potent -sulfonamido-2-phenylbenzoxazoles (PBZs), we established the binding site of the PBZ molecules using cryo-EM and found that GroEL was the cellular target responsible for the mode of action. Cryo-EM revealed that PBZ1587 binds at the GroEL ring-ring interface (RRI). A cellular reporter assay confirmed that PBZ1587 engaged GroEL in cells, but cellular rescue experiments showed potential off-target effects. This prompted us to explore a closely related analogue, PBZ1038, which is also bound to the RRI. Biochemical characterization showed potent inhibition of Gram-negative chaperonins but much lower potency of chaperonin from a Gram-positive organism, . A cellular reporter assay showed that PBZ1038 also engaged GroEL in cells and that the cytotoxic phenotype could be rescued by a chromosomal copy of GroEL/GroES or by expressing a recalcitrant RRI mutant. These data argue that PBZ1038's antimicrobial action is exerted through inhibition of GroES/GroEL, validating this chaperone system as an antibiotic target.
History
DepositionMay 25, 2024Deposition site: RCSB / Processing site: RCSB
Revision 1.0Aug 7, 2024Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
H: 60 kDa chaperonin
O: 60 kDa chaperonin
I: 60 kDa chaperonin
P: 60 kDa chaperonin
J: 60 kDa chaperonin
Q: 60 kDa chaperonin
K: 60 kDa chaperonin
R: 60 kDa chaperonin
L: 60 kDa chaperonin
S: 60 kDa chaperonin
M: 60 kDa chaperonin
T: 60 kDa chaperonin
N: 60 kDa chaperonin
U: 60 kDa chaperonin
hetero molecules


Theoretical massNumber of molelcules
Total (without water)807,51021
Polymers803,48414
Non-polymers4,0267
Water00
1


  • Idetical with deposited unit
  • defined by author&software
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_555x,y,z1

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Components

#1: Protein
60 kDa chaperonin / GroEL protein / Protein Cpn60


Mass: 57391.711 Da / Num. of mol.: 14
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Escherichia coli (E. coli)
Gene: groEL, groL, mopA, BN17_41231, BU34_16740, ECs5124, LF82_0923
Production host: Escherichia coli (E. coli) / References: UniProt: Q548M1
#2: Chemical
ChemComp-A1AS6 / N-(2-{4-[4-(aminomethyl)benzene-1-sulfonamido]phenyl}-1,3-benzoxazol-5-yl)-5-chlorothiophene-2-sulfonamide


Mass: 575.079 Da / Num. of mol.: 7 / Source method: obtained synthetically / Formula: C24H19ClN4O5S3 / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: E.coli GroEL + PBZ1587 inhibitor / Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Source (natural)Organism: Escherichia coli (E. coli)
Source (recombinant)Organism: Escherichia coli (E. coli)
Buffer solutionpH: 7.4
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
VitrificationCryogen name: ETHANE

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Electron microscopy imaging

Experimental equipment
Model: Talos Arctica / Image courtesy: FEI Company
MicroscopyModel: FEI TALOS ARCTICA
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 200 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal defocus max: 1500 nm / Nominal defocus min: 500 nm
Image recordingElectron dose: 62.5 e/Å2 / Film or detector model: GATAN K2 SUMMIT (4k x 4k)

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Processing

CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
3D reconstructionResolution: 3.26 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 20659 / Symmetry type: POINT
Refine LS restraints
Refine-IDTypeDev idealNumber
ELECTRON MICROSCOPYf_bond_d0.00354649
ELECTRON MICROSCOPYf_angle_d0.60873829
ELECTRON MICROSCOPYf_dihedral_angle_d3.8847973
ELECTRON MICROSCOPYf_chiral_restr0.048946
ELECTRON MICROSCOPYf_plane_restr0.0039884

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