8OIX

CryoEM structure of 20S Trichomonas vaginalis proteasome in complex with proteasome inhibitor Salinosporamid A

8OIX の概要

• エントリーDOI: 10.2210/pdb8oix/pdb
• EMDBエントリー: 16901
• 分子名称: Family T1, proteasome alpha subunit, threonine peptidase, Proteasome subunit beta, Family T1, proteasome beta subunit, threonine peptidase, ... (15 entities in total)
• 機能のキーワード: proteasome, 20s, trichomonas vaginalis, covalently bound salinosporamide a, marizomib, hydrolase
• 由来する生物種: Trichomonas vaginalis G3; 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 708405.66

構造登録者

Silhan, J.,Fajtova, P.,Boura, E. (登録日: 2023-03-23, 公開日: 2024-04-10, 最終更新日: 2024-10-23)

主引用文献

Silhan, J.,Fajtova, P.,Bartosova, J.,Hurysz, B.M.,Almaliti, J.,Miyamoto, Y.,Eckmann, L.,Gerwick, W.H.,O'Donoghue, A.J.,Boura, E.
Structural elucidation of recombinant Trichomonas vaginalis 20S proteasome bound to covalent inhibitors.
Nat Commun, 15:8621-8621, 2024

PubMed 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.

PubMed: 39366995
DOI: 10.1038/s41467-024-53022-w

実験手法

ELECTRON MICROSCOPY (2.89 Å)