PXD069687

PXD069687 is an original dataset announced via ProteomeXchange.

Title	TMPRSS2-mediated coronavirus spike activation and inhibition
Description	The human protease TMPRSS2 facilitates entry of many respiratory viruses into cells, including coronaviruses and influenza viruses, yet its mechanism or viral glycoprotein recognition remains unclear. Here, we show that following ACE2 engagement and formation of an early fusion intermediate SARS-CoV-2 spike (S) conformation (E-FIC), TMPRSS2 cleaves the R815 S2' site and triggers large-scale conformational changes required for membrane fusion and viral entry. Using cryo-electron microscopy, we resolve the interactions between TMPRSS2 and S2' and identify key residues modulating binding specificity. We further reveal that S2' site-directed broadly neutralizing antibodies recognise E-FIC and inhibit viral entry by interfering with TMPRSS2 access. We describe a TMPRSS2-directed monoclonal antibody that inhibits entry of several coronaviruses into TMPRSS2 expressing cells and protects against SARS-CoV-2 challenge in vivo. These results elucidate the mechanistic role of TMPRSS2 andS2' site-directed broadly neutralizing antibodies in coronavirus entry, and establish host-directed counter-measures as a paradigm for viral pandemic preparedness.
HostingRepository	PRIDE
AnnounceDate	2026-03-27
AnnouncementXML	Submission_2026-03-27_08:35:40.490.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Emmajay Sutherland
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	iodoacetamide derivatized residue
Instrument	Orbitrap Ascend

Revision	Datetime	Status	ChangeLog Entry
0	2025-10-20 17:25:46	ID requested
⏵ 1	2026-03-27 08:35:40	announced

Dataset with its publication pending

submitter keyword: SARS-CoV-2

Nicholas M. Riley
contact affiliation	Department of Chemistry, University of Washington, Seattle, Washington 98195, United States
contact email	nmriley@uw.edu
lab head
Emmajay Sutherland
contact affiliation	University of Washington
contact email	emmajay.sutherland@gmail.com
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD069687
     1. Label: PRIDE project
     2. Name: TMPRSS2-mediated coronavirus spike activation and inhibition