6TCZ

Leishmania tarentolae proteasome 20S subunit complexed with LXE408

6TCZ の概要

• エントリーDOI: 10.2210/pdb6tcz/pdb
• EMDBエントリー: 10462
• 分子名称: Proteasome subunit alpha type, Proteasome subunit beta, Proteasome subunit family protein, ... (15 entities in total)
• 機能のキーワード: proteasome complex, inhibitor, peptidase, hydrolase
• 由来する生物種: Leishmania donovani; 詳細
• タンパク質・核酸の鎖数: 28
• 化学式量合計: 848731.37

構造登録者

Srinivas, H. (登録日: 2019-11-07, 公開日: 2020-08-26, 最終更新日: 2024-05-22)

主引用文献

Nagle, A.,Biggart, A.,Be, C.,Srinivas, H.,Hein, A.,Caridha, D.,Sciotti, R.J.,Pybus, B.,Kreishman-Deitrick, M.,Bursulaya, B.,Lai, Y.H.,Gao, M.Y.,Liang, F.,Mathison, C.J.N.,Liu, X.,Yeh, V.,Smith, J.,Lerario, I.,Xie, Y.,Chianelli, D.,Gibney, M.,Berman, A.,Chen, Y.L.,Jiricek, J.,Davis, L.C.,Liu, X.,Ballard, J.,Khare, S.,Eggimann, F.K.,Luneau, A.,Groessl, T.,Shapiro, M.,Richmond, W.,Johnson, K.,Rudewicz, P.J.,Rao, S.P.S.,Thompson, C.,Tuntland, T.,Spraggon, G.,Glynne, R.J.,Supek, F.,Wiesmann, C.,Molteni, V.
Discovery and Characterization of Clinical Candidate LXE408 as a Kinetoplastid-Selective Proteasome Inhibitor for the Treatment of Leishmaniases.
J.Med.Chem., 63:10773-10781, 2020

PubMed Abstract: Visceral leishmaniasis is responsible for up to 30,000 deaths every year. Current treatments have shortcomings that include toxicity and variable efficacy across endemic regions. Previously, we reported the discovery of GNF6702, a selective inhibitor of the kinetoplastid proteasome, which cleared parasites in murine models of leishmaniasis, Chagas disease, and human African trypanosomiasis. Here, we describe the discovery and characterization of LXE408, a structurally related kinetoplastid-selective proteasome inhibitor currently in Phase 1 human clinical trials. Furthermore, we present high-resolution cryo-EM structures of the proteasome in complex with LXE408, which provides a compelling explanation for the noncompetitive mode of binding of this novel class of inhibitors of the kinetoplastid proteasome.

PubMed: 32667203
DOI: 10.1021/acs.jmedchem.0c00499

実験手法

ELECTRON MICROSCOPY (3.4 Å)