PXD023751

PXD023751 is an original dataset announced via ProteomeXchange.

Title	Covalent histone modification by an electrophilic derivative of the anti-HIV drug nevirapine
Description	Nevirapine (NVP), a non-nucleoside reverse transcriptase inhibitor widely used in combined antiretroviral therapy and to prevent mother-to-child transmission of the human immunodefi-ciency virus type 1, is associated with several adverse side effects. Using 12-mesyloxy-nevirapine, a model electrophile of the reactive metabolites derived from the NVP Phase I metabolite, 12-hydroxy-NVP, we demonstrate that the nucleophilic core and C-terminal residues of histones are targets for covalent adduct formation. We identified multiple NVP-modification sites at lysine (e.g. H2BK47, H4K32), histidine (e.g. H2BH110, H4H76) and serine (e.g. H2BS33) residues of the four histones using a mass spectrometry-based bottom-up proteomic analysis. In particular, H2BK47, H2BH110, H2AH83 and H4H76 were evidenced to be potential hot spots for NVP incorporation. In fact, a remarkable selectivity to the imidazole ring of histidine was observed: 3 out of the 11 histidine residues of histones were NVP-modified. This suggests that NVP-modified histidine residues of histones are prospective markers of this an-ti-HIV drug bioactivation and/or toxicity. Importantly, NVP-derived modifications were iden-tified at sites known to determine chromatin structure (e.g. H4H76) and that can undergo multi-ple types of PTMs (e.g. H2BK47, H4H76). These results open new insights into the molecular mechanisms of drug-induced adverse reactions.
HostingRepository	PRIDE
AnnounceDate	2021-03-08
AnnouncementXML	Submission_2021-03-07_22:24:01.530.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	guadalupe espadas
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue
Instrument	LTQ Orbitrap

Revision	Datetime	Status	ChangeLog Entry
0	2021-01-22 06:42:41	ID requested
⏵ 1	2021-03-07 22:24:01	announced

Dataset with its publication pending

ProteomeXchange project tag: PRIME-XS Project

submitter keyword: covalent histone modification

mass spectrometry

drug-induced adverse reactions

covalent protein adducts

nevirapine

Eduard Sabidó
contact affiliation	Head of the CRG/UPF Proteomics Unit
contact email	eduard.sabido@crg.eu
lab head
guadalupe espadas
contact affiliation	crg
contact email	guadalupe.espadas@crg.eu
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/2021/03/PXD023751

PRIDE project URI

• PRIDE
  1. PXD023751
     1. Label: PRIDE project
     2. Name: Covalent histone modification by an electrophilic derivative of the anti-HIV drug nevirapine