7WEU

Crystal structure of Peroxiredoxin I in complex with compound 19-048

7WEU の概要

• エントリーDOI: 10.2210/pdb7weu/pdb
• 分子名称: Peroxiredoxin-1, UNKNOWN LIGAND (3 entities in total)
• 機能のキーワード: inhibitor, complex, peroxiredoxin, oxidoreductase
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 38777.25

構造登録者

Zhang, H.,Luo, C. (登録日: 2021-12-24, 公開日: 2022-12-28, 最終更新日: 2023-11-29)

主引用文献

Xu, H.,Zhao, H.,Ding, C.,Jiang, D.,Zhao, Z.,Li, Y.,Ding, X.,Gao, J.,Zhou, H.,Luo, C.,Chen, G.,Zhang, A.,Xu, Y.,Zhang, H.
Celastrol suppresses colorectal cancer via covalent targeting peroxiredoxin 1.
Signal Transduct Target Ther, 8:51-51, 2023

PubMed Abstract: As a terpenoids natural product isolated from the plant Thunder God Vine, Celastrol is widely studied for its pharmacological activities, including anti-tumor activities. The clinical application of Celastrol is strictly limited due to its severe side effects, whereas previously revealed targets and mechanism of Celastrol seldom reduce its in vivo toxicity via structural optimization. Target identification has a far-reaching influence on the development of innovative drugs, and omics data has been widely used for unbiased target prediction. However, it is difficult to enrich target of specific phenotype from thousands of genes or proteins, especially for natural products with broad promising activities. Here, we developed a text-mining-based web-server tool to enrich targets from omics data of inquired compounds. Then peroxiredoxin 1 (PRDX1) was identified as the ROS-manipulating target protein of Celastrol in colorectal cancer. Our solved high-resolution crystal structure revealed the unique covalent binding mode of Celastrol with PRDX1. New derivative compound 19-048 with improved potency against PRDX1 and selectivity towards PRDX2~PRDX6 were synthesized based on crystal structure analysis. Both Celastrol and 19-048 effectively suppressed the proliferation of colorectal cancer cells. The anti-tumor efficacy of Celastrol and 19-048 was significantly diminished on xenograft nude mice bearing PRDX1 knock-down colorectal cancer cells. Several downstream genes of p53 signaling pathway were dramatically up-regulated with Celastrol or 19-048 treatment. Our findings reveal that the side effects of Celastrol could be reduced via structural modification, and PRDX1 inhibition is promising for the treatment of colorectal cancer.

PubMed: 36732502
DOI: 10.1038/s41392-022-01231-4

実験手法

X-RAY DIFFRACTION (1.81 Å)