8UD9

Structure of human constitutive 20S proteasome complexed with the inhibitor TDI-8304

8UD9 の概要

• エントリーDOI: 10.2210/pdb8ud9/pdb
• 関連するPDBエントリー: 8G6E 8G6F
• EMDBエントリー: 42148
• 分子名称: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (16 entities in total)
• 機能のキーワード: 20s proteasome, inhibitor, human, complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 718946.82

構造登録者

Hsu, H.-C.,Li, H. (登録日: 2023-09-28, 公開日: 2023-12-20, 最終更新日: 2024-01-03)

主引用文献

Hsu, H.C.,Li, D.,Zhan, W.,Ye, J.,Liu, Y.J.,Leung, A.,Qin, J.,Crespo, B.,Gamo, F.J.,Zhang, H.,Cui, L.,Roth, A.,Kirkman, L.A.,Li, H.,Lin, G.
Structures revealing mechanisms of resistance and collateral sensitivity of Plasmodium falciparum to proteasome inhibitors.
Nat Commun, 14:8302-8302, 2023

PubMed Abstract: The proteasome of the malaria parasite Plasmodium falciparum (Pf20S) is an advantageous drug target because its inhibition kills P. falciparum in multiple stages of its life cycle and synergizes with artemisinins. We recently developed a macrocyclic peptide, TDI-8304, that is highly selective for Pf20S over human proteasomes and is potent in vitro and in vivo against P. falciparum. A mutation in the Pf20S β6 subunit, A117D, confers resistance to TDI-8304, yet enhances both enzyme inhibition and anti-parasite activity of a tripeptide vinyl sulfone β2 inhibitor, WLW-vs. Here we present the high-resolution cryo-EM structures of Pf20S with TDI-8304, of human constitutive proteasome with TDI-8304, and of Pf20Sβ6 with WLW-vs that give insights into the species selectivity of TDI-8304, resistance to it, and the collateral sensitivity associated with resistance, including that TDI-8304 binds β2 and β5 in wild type Pf20S as well as WLW-vs binds β2 and β5 in Pf20Sβ6. We further show that TDI-8304 kills P. falciparum as quickly as chloroquine and artemisinin and is active against P. cynomolgi at the liver stage. This increases interest in using these structures to facilitate the development of Pf20S inhibitors that target multiple proteasome subunits and limit the emergence of resistance.

PubMed: 38097652
DOI: 10.1038/s41467-023-44077-2

実験手法

ELECTRON MICROSCOPY (2.04 Å)