PXD036325

PXD036325 is an original dataset announced via ProteomeXchange.

Title	A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations
Description	The SARS-CoV-2 main protease (Mpro) is a major therapeutic target. The Mpro inhibitor, nirmatrelvir, is the antiviral component of Paxlovid, an orally available treatment for COVID-19. As Mpro inhibitor use increases, drug resistant mutations will likely emerge. We have established a non-pathogenic system, in which yeast growth serves as a proxy for Mpro activity, enabling rapid identification of mutants with altered enzymatic activity and drug sensitivity. The E166 residue is known to be a potential hot spot for drug resistance and yeast assays showed that an E166R substitution conferred strong nirmatrelvir resistance while an E166N mutation compromised activity. On the other hand, N142A and P132H mutations caused little to no change in drug response and activity. Standard enzymatic assays confirmed the yeast results. In turn, we solved the structures of Mpro E166R, and Mpro E166N, providing insights into how arginine may drive drug resistance while asparagine leads to reduced activity. The work presented here will help characterize novel resistant variants of Mpro that may arise as Mpro antivirals become more widely used.
HostingRepository	PRIDE
AnnounceDate	2023-08-08
AnnouncementXML	Submission_2023-08-08_13:45:02.746.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD036325
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	PaulLanglais
SpeciesList	scientific name: Caenorhabditis elegans; NCBI TaxID: 6239; scientific name: Saccharomyces cerevisiae; NCBI TaxID: NCBITaxon:4932;
ModificationList	phosphorylated residue; acetylated residue; monohydroxylated residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-08-26 07:18:57	ID requested
⏵ 1	2023-08-08 13:45:03	announced

10.6019/PXD036325;

ProteomeXchange project tag: Sars-cov-2, Covid-19

submitter keyword: COVID-19

JohnChoy
contact affiliation	Department of Biology, Catholic University of America
contact email	choy@cua.edu
lab head
PaulLanglais
contact affiliation	University of Arizona
contact email	langlais@deptofmed.arizona.edu
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/2023/08/PXD036325

PRIDE project URI

• PRIDE
  1. PXD036325
     1. Label: PRIDE project
     2. Name: A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations