PXD036325 is an
original dataset announced via ProteomeXchange.
Dataset Summary
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 |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
0 | 2022-08-26 07:18:57 | ID requested | |
⏵ 1 | 2023-08-08 13:45:03 | announced | |
Publication List
Keyword List
ProteomeXchange project tag: Sars-cov-2, Covid-19 |
submitter keyword: COVID-19 |
Contact List
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 | |
Full Dataset Link List
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD036325
- Label: PRIDE project
- Name: A yeast-based system to study SARS-CoV-2 Mpro structure and to identify nirmatrelvir resistant mutations