PXD045453

PXD045453 is an original dataset announced via ProteomeXchange.

Title	Structure of Staphylococcus aureus ClpP bound to the covalent active site inhibitor Cystargolide A
Description	The caseinolytic protease is a highly conserved serine protease, seminal in prokaryotic and eukaryotic protein homeostasis and regulatory proteolysis, and a promising antibacterial and anticancer drug target. Here, we describe the cystargolides as potent and the first natural β-lactone inhibitors of the proteolytic core ClpP. Based on the discovery of two clpP genes next to the cystargolide biosynthetic genes in Kitasatospora cystarginea, we explored ClpP as a potential cystargolide target. We show covalent inhibition of Staphylococcus aureus ClpP by cystargolide A and B by different biochemical methods in vitro. Synthesis of semi-synthetic derivatives with improved cell permeability allowed us to confirm ClpP as a specific target within intact S. aureus cells and to demonstrate anti-virulence activity. In Streptomycetes griseus growth inhibition occurs. Crystal structures show cystargolide A covalently bound to all 14 active sites of S. aureus ClpP. Although synthetic β-lactones are known as the pioneering group of ClpP inhibitors, their co-crystallisation has not been successful, so far. The cystargolides now reveal the molecular mechanism of ClpP inhibition by β-lactone inhibitors.
HostingRepository	PRIDE
AnnounceDate	2023-11-30
AnnouncementXML	Submission_2023-11-30_06:50:50.438.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Markus Lakemeyer
SpeciesList	scientific name: Staphylococcus aureus; NCBI TaxID: 1280;
ModificationList	iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2023-09-18 05:22:23	ID requested
⏵ 1	2023-11-30 06:50:50	announced

10.1002/ANIE.202314028;

submitter keyword: Antibacterials, Chemmical Proteomics, Proteases

Heike Brötz-Oesterhelt
contact affiliation	Prof. Dr. H. Brötz-Oesterhelt Department of Microbial Bioactive Compounds, Interfaculty Institute of Microbiology and Infection Medicine Cluster of Excellence Controlling Microbes to Fight Infections University of Tübingen Auf der Morgenstelle 28, 72076 Tübingen, Germany
contact email	heike.broetz-oesterhelt@uni-tuebingen.de
lab head
Markus Lakemeyer
contact affiliation	Institute for Organic and Macromolecular Chemistry Friedrich-Schiller-University Jena
contact email	markus.lakemeyer@uni-jena.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD045453
     1. Label: PRIDE project
     2. Name: Structure of Staphylococcus aureus ClpP bound to the covalent active site inhibitor Cystargolide A