5L87

Targeting the PEX14-PEX5 interaction by small molecules provides novel therapeutic routes to treat trypanosomiases.

5L87 の概要

• エントリーDOI: 10.2210/pdb5l87/pdb
• 関連するPDBエントリー: 2W84
• 分子名称: Peroxin 14, 5-(1~{H}-indol-3-ylmethyl)-1-methyl-~{N}-(naphthalen-1-ylmethyl)-6,7-dihydro-4~{H}-pyrazolo[4,3-c]pyridine-3-carboxamide, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: trypanosomiasis, glycosome, protein-protein interaction inhibitor, structure-based drug discovery, inhibitor, membrane protein
• 由来する生物種: Trypanosoma brucei brucei
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 8394.69

構造登録者

Dawidowski, M.,Emmanouilidis, L.,Sattler, M.,Popowicz, G.M. (登録日: 2016-06-07, 公開日: 2017-03-08, 最終更新日: 2024-01-10)

主引用文献

Dawidowski, M.,Emmanouilidis, L.,Kalel, V.C.,Tripsianes, K.,Schorpp, K.,Hadian, K.,Kaiser, M.,Maser, P.,Kolonko, M.,Tanghe, S.,Rodriguez, A.,Schliebs, W.,Erdmann, R.,Sattler, M.,Popowicz, G.M.
Inhibitors of PEX14 disrupt protein import into glycosomes and kill Trypanosoma parasites.
Science, 355:1416-1420, 2017

PubMed Abstract: The parasitic protists of the genus infect humans and domestic mammals, causing severe mortality and huge economic losses. The most threatening trypanosomiasis is Chagas disease, affecting up to 12 million people in the Americas. We report a way to selectively kill by blocking glycosomal/peroxisomal import that depends on the PEX14-PEX5 protein-protein interaction. We developed small molecules that efficiently disrupt the PEX14-PEX5 interaction. This results in mislocalization of glycosomal enzymes, causing metabolic catastrophe, and it kills the parasite. High-resolution x-ray structures and nuclear magnetic resonance data enabled the efficient design of inhibitors with trypanocidal activities comparable to approved medications. These results identify PEX14 as an "Achilles' heel" of the suitable for the development of new therapies against trypanosomiases and provide the structural basis for their development.

PubMed: 28360328
DOI: 10.1126/science.aal1807

実験手法

X-RAY DIFFRACTION (0.87 Å)