8JHZ

Cryo-EM structure of the TcsH-TMPRSS2 complex

Summary for 8JHZ

• Entry DOI: 10.2210/pdb8jhz/pdb
• EMDB information: 36301
• Descriptor: Hemorrhagic toxin, Transmembrane protease serine 2, ZINC ION (3 entities in total)
• Functional Keywords: tcsh, tmpess2, toxin/hydrolase, toxin-hydrolase complex
• Biological source: Paeniclostridium sordellii (Clostridium sordellii); More
• Total number of polymer chains: 2
• Total formula weight: 347453.61

Authors

Zhou, R.,Liang, T.,Zhan, X. (deposition date: 2023-05-25, release date: 2024-03-20, Last modification date: 2025-07-23)

Primary citation

Zhou, R.,He, L.,Zhang, J.,Zhang, X.,Li, Y.,Zhan, X.,Tao, L.
Molecular basis of TMPRSS2 recognition by Paeniclostridium sordellii hemorrhagic toxin.
Nat Commun, 15:1976-1976, 2024

PubMed Abstract: Hemorrhagic toxin (TcsH) is a major virulence factor produced by Paeniclostridium sordellii, which is a non-negligible threat to women undergoing childbirth or abortions. Recently, Transmembrane Serine Protease 2 (TMPRSS2) was identified as a host receptor of TcsH. Here, we show the cryo-EM structures of the TcsH-TMPRSS2 complex and uncover that TcsH binds to the serine protease domain (SPD) of TMPRSS2 through the CROP unit-VI. This receptor binding mode is unique among LCTs. Five top surface loops of TMPRSS2, which also determine the protease substrate specificity, constitute the structural determinants recognized by TcsH. The binding of TcsH inhibits the proteolytic activity of TMPRSS2, whereas its implication in disease manifestations remains unclear. We further show that mutations selectively disrupting TMPRSS2-binding reduce TcsH toxicity in the intestinal epithelium of the female mice. These findings together shed light on the distinct molecular basis of TcsH-TMPRSS2 interactions, which expands our knowledge of host recognition mechanisms employed by LCTs and provides novel targets for developing therapeutics against P. sordellii infections.

PubMed: 38438396
DOI: 10.1038/s41467-024-46394-6

Experimental method

ELECTRON MICROSCOPY (3.2 Å)