PXD042384

PXD042384 is an original dataset announced via ProteomeXchange.

Title	Peptide-Based Covalent Inhibitors Bearing Mild Electrophiles to Target a Conserved His Residue of the Bacterial Sliding Clamp
Description	Bacterial infections caused by drug-resistant pathogens represent a major threat against which effective antibiotics acting via new mechanisms and engaging new biological targets are highly needed. The sliding clamp (SC), an essential component of the bacterial DNA replication machinery, has been identified as a new target. This processivity factor operates through multiple protein-protein interactions with conserved peptide motifs in multiple proteins involved in DNA replication and repair. Herein, we report the structure-guided design of targeted covalent inhibitors (TCIs) able to bind covalently and selectively to the E. coli SC (EcSC). The inhibitors target His175, a well-conserved SC residue located on the edge of the peptide-binding pocket. Thermodynamic and kinetic analyses confirmed the higher efficiency of the chloroacetamide warhead compared to Michael acceptors. High-resolution X-ray structures of two different covalent inhibitor–SC adducts revealed the canonical ligand orientation and confirmed the formation of the covalent bond with His175. Proteomic studies were consistent with a selective EcSC engagement by the chloroacetamide-based TCI. Finally, the TCI of SC was substantially more active than the parent non-covalent inhibitor in an in vitro SC-dependent replicative assay, suggesting the potential of the approach to target the SC of priority pathogens.
HostingRepository	PRIDE
AnnounceDate	2024-01-29
AnnouncementXML	Submission_2024-01-29_04:56:46.002.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD042384
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Johana Chicher
SpeciesList	scientific name: Escherichia coli; NCBI TaxID: 562;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-05-22 00:20:24	ID requested
⏵ 1	2024-01-29 04:56:46	announced

10.1021/JACSAU.3C00572;

10.6019/PXD042384;

submitter keyword: sliding clamp, peptide inhibito ,Bacteria

Jérôme Wagner
contact affiliation	Université de Strasbourg, CNRS, Architecture et Réactivité de l’ARN, UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, 2 allée K. Roentgen 67084 Strasbourg, France
contact email	j.wagner@ibmc-cnrs.unistra.fr
lab head
Johana Chicher
contact affiliation	Université de Strasbourg, Plateforme Protéomique Strasbourg-Esplanade, Centre National de la Recherche Scientifique
contact email	j.chicher@ibmc-cnrs.unistra.fr
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD042384
     1. Label: PRIDE project
     2. Name: Peptide-Based Covalent Inhibitors Bearing Mild Electrophiles to Target a Conserved His Residue of the Bacterial Sliding Clamp