6CXS

Crystal Structure of Clostridium perfringens beta-glucuronidase bound with a novel, potent inhibitor 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine

6CXS の概要

• エントリーDOI: 10.2210/pdb6cxs/pdb
• 関連するPDBエントリー: 4JKM
• 分子名称: Beta-glucuronidase, Maltose/maltodextrin-binding periplasmic protein, 4-(8-(piperazin-1-yl)-1,2,3,4-tetrahydro-[1,2,3]triazino[4',5':4,5]thieno[2,3-c]isoquinolin-5-yl)morpholine, ... (4 entities in total)
• 機能のキーワード: hydrolase-hydrolase-inhibitor complex, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Clostridium perfringens (strain 13 / Type A); 詳細
• タンパク質・核酸の鎖数: 4
• 化学式量合計: 226983.78

構造登録者

Wallace, B.D.,Redinbo, M.R. (登録日: 2018-04-04, 公開日: 2019-04-17, 最終更新日: 2023-10-04)

主引用文献

Bhatt, A.P.,Pellock, S.J.,Biernat, K.A.,Walton, W.G.,Wallace, B.D.,Creekmore, B.C.,Letertre, M.M.,Swann, J.R.,Wilson, I.D.,Roques, J.R.,Darr, D.B.,Bailey, S.T.,Montgomery, S.A.,Roach, J.M.,Azcarate-Peril, M.A.,Sartor, R.B.,Gharaibeh, R.Z.,Bultman, S.J.,Redinbo, M.R.
Targeted inhibition of gut bacterial beta-glucuronidase activity enhances anticancer drug efficacy.
Proc.Natl.Acad.Sci.USA, 2020

PubMed Abstract: Irinotecan treats a range of solid tumors, but its effectiveness is severely limited by gastrointestinal (GI) tract toxicity caused by gut bacterial β-glucuronidase (GUS) enzymes. Targeted bacterial GUS inhibitors have been shown to partially alleviate irinotecan-induced GI tract damage and resultant diarrhea in mice. Here, we unravel the mechanistic basis for GI protection by gut microbial GUS inhibitors using in vivo models. We use in vitro, in fimo, and in vivo models to determine whether GUS inhibition alters the anticancer efficacy of irinotecan. We demonstrate that a single dose of irinotecan increases GI bacterial GUS activity in 1 d and reduces intestinal epithelial cell proliferation in 5 d, both blocked by a single dose of a GUS inhibitor. In a tumor xenograft model, GUS inhibition prevents intestinal toxicity and maintains the antitumor efficacy of irinotecan. Remarkably, GUS inhibitor also effectively blocks the striking irinotecan-induced bloom of Enterobacteriaceae in immune-deficient mice. In a genetically engineered mouse model of cancer, GUS inhibition alleviates gut damage, improves survival, and does not alter gut microbial composition; however, by allowing dose intensification, it dramatically improves irinotecan's effectiveness, reducing tumors to a fraction of that achieved by irinotecan alone, while simultaneously promoting epithelial regeneration. These results indicate that targeted gut microbial enzyme inhibitors can improve cancer chemotherapeutic outcomes by protecting the gut epithelium from microbial dysbiosis and proliferative crypt damage.

PubMed: 32170007
DOI: 10.1073/pnas.1918095117

実験手法

X-RAY DIFFRACTION (2.8 Å)