PXD034921

PXD034921 is an original dataset announced via ProteomeXchange.

Title	Direct capture, inhibition and crystal structure of HsaD (Rv3569c) from M. tuberculosis by Cycliphostin & Cyclipostins analogs
Description	Tuberculosis (TB) which is one of the deadliest infectious disease worldwide, is caused by the inhalation of the pathogenic bacteria Mycobacterium tuberculosis. Since many years now, the emergence of multiple (MDR), extensively (XDR) and totally (TDR) drug resistant strains amplifies the incidences of TB resulting in failure of treatment and death. However, no new TB drug classes have been developed or approved for drug susceptible TB since the current 6-month four-drug combination was introduced in the 1970s. Most of the promising new molecules in development are either repurposed drug compounds or new derivatives of known anti-mycobacterial drugs that mainly target the bacteria cell wall biosynthesis. It is now acknowledged that microbial lipolytic enzymes are involved in bacterial growth, cell wall biosynthesis, carbon sources management and virulence during infections by M. tuberculosis. Although no drug is reported to target specifically enzymes involved in mycobacterial intracellular lipid metabolism; our results have clearly shown that mycobacterial enzymes can be potential therapeutic targets. Consequently, specific inhibitors of such enzymes might turn out to be valuable anti-tuberculous agents. We previously reported that the Cyclophostin & Cyclipostins (CyC) analogs are a new family of potent antimycobacterial molecules which react specifically and covalently with (Ser/Cys)-based enzymes. Competitive ABPP approach with CyC17-pretreated M. tb lysate and the ActivX Desthiobiotin-FP activity-based probe (ABP) allowed identifying 23 distinct proteins as potential targets of this inhibitor, that were all (Ser/Cys)-based enzymes, most of them participating in M. tb lipid metabolism and cell wall biosynthesis. However, this approach for target identification in cell lysates is mostly indirect with the risk of false positive hits, and cannot be applied in vivo for various technical reasons, the main one being the need for a large number of compounds and cells. To overcome these issues, we report here the synthesis of new CyC alkyne-containing inhibitors (i.e., CyCyne) analogous to CyC17, and their use for the direct fishing of target proteins in living M. tb via bio-orthogonal click-chemistry activity-based protein profiling (CC-ABPP) strategy. In particular, we further explore and validate, through a combination of biochemical and structural approaches, the specificity of inhibition of the HsaD activity by the CyC analogs.
HostingRepository	PRIDE
AnnounceDate	2022-09-20
AnnouncementXML	Submission_2022-09-20_03:28:48.263.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	AUDEBERT Stephane
SpeciesList	scientific name: Mycobacterium tuberculosis H37Rv; NCBI TaxID: 83332;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive Plus

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-26 07:47:53	ID requested
⏵ 1	2022-09-20 03:28:48	announced

Dataset with its publication pending

submitter keyword: LC-MSMS

Drug susceptibility

activity based-protein profiling

proteomic analysis

biochemical characterization

3D structure

Dr Jean-François CAVALIER
contact affiliation	Aix-Marseille Univ, CNRS, LISM, IMM FR3479, 13009 Marseille, France
contact email	jfcavalier@imm.cnrs.fr
lab head
AUDEBERT Stephane
contact affiliation	Marseille Proteomic, Centre de Recherche en Cancérologie de Marseille, Inserm UMR1068, CNRS UMR7258, Aix Marseille Université U105, Institut Paoli Calmettes, 27 Boulevard Leï Roure CS30059 13273 Marseille Cedex 09 France
contact email	stephane.audebert@inserm.fr
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2022/09/PXD034921

PRIDE project URI

• PRIDE
  1. PXD034921
     1. Label: PRIDE project
     2. Name: Direct capture, inhibition and crystal structure of HsaD (Rv3569c) from M. tuberculosis by Cycliphostin & Cyclipostins analogs