Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors

Jan Silhan, Pavla Fajtova (), Jitka Bartosova, Brianna M. Hurysz, Jehad Almaliti, Yukiko Miyamoto, Lars Eckmann, William H. Gerwick, Anthony J. O’Donoghue () and Evzen Boura ()
Additional contact information
Jan Silhan: v.v.i.
Pavla Fajtova: v.v.i.
Jitka Bartosova: v.v.i.
Brianna M. Hurysz: University of California San Diego
Jehad Almaliti: The University of Jordan
Yukiko Miyamoto: University of California San Diego
Lars Eckmann: University of California San Diego
William H. Gerwick: University of California San Diego
Anthony J. O’Donoghue: University of California San Diego
Evzen Boura: v.v.i.

Nature Communications, 2024, vol. 15, issue 1, 1-12

Abstract: Abstract The proteasome is a proteolytic enzyme complex essential for protein homeostasis in mammalian cells and protozoan parasites like Trichomonas vaginalis (Tv), the cause of the most common, non-viral sexually transmitted disease. Tv and other protozoan 20S proteasomes have been validated as druggable targets for antimicrobials. However, low yields and purity of the native proteasome have hindered studies of the Tv 20S proteasome (Tv20S). We address this challenge by creating a recombinant protozoan proteasome by expressing all seven α and seven β subunits of Tv20S alongside the Ump-1 chaperone in insect cells. The recombinant Tv20S displays biochemical equivalence to its native counterpart, confirmed by various assays. Notably, the marizomib (MZB) inhibits all catalytic subunits of Tv20S, while the peptide inhibitor carmaphycin-17 (CP-17) specifically targets β2 and β5. Cryo-electron microscopy (cryo-EM) unveils the structures of Tv20S bound to MZB and CP-17 at 2.8 Å. These findings explain MZB’s low specificity for Tv20S compared to the human proteasome and demonstrate CP-17’s higher specificity. Overall, these data provide a structure-based strategy for the development of specific Tv20S inhibitors to treat trichomoniasis.

Date: 2024
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-024-53022-w Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-53022-w

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-024-53022-w

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().