7MDC

Full-length wildtype ClbP inhibited by hexanoyl-D-asparagine boronic acid

7MDC の概要

• エントリーDOI: 10.2210/pdb7mdc/pdb
• 関連するPDBエントリー: 7MDE 7MDF 7UL6
• 分子名称: Beta-lactamase, NONAETHYLENE GLYCOL, DIMETHYL SULFOXIDE, ... (8 entities in total)
• 機能のキーワード: colibactin peptidase, s12 peptidase, boronic acid inhibitor, hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Escherichia coli
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 56711.25

構造登録者

Velilla, J.A.,Volpe, M.R.,Gaudet, R. (登録日: 2021-04-03, 公開日: 2022-09-28, 最終更新日: 2024-10-16)

主引用文献

Volpe, M.R.,Velilla, J.A.,Daniel-Ivad, M.,Yao, J.J.,Stornetta, A.,Villalta, P.W.,Huang, H.C.,Bachovchin, D.A.,Balbo, S.,Gaudet, R.,Balskus, E.P.
A small molecule inhibitor prevents gut bacterial genotoxin production.
Nat.Chem.Biol., 19:159-167, 2023

PubMed Abstract: The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis.

PubMed: 36253549
DOI: 10.1038/s41589-022-01147-8

実験手法

X-RAY DIFFRACTION (2.7 Å)