4YQM

Glutathione S-transferase Omega 1 bound to covalent inhibitor C1-27

4YQM の概要

• エントリーDOI: 10.2210/pdb4yqm/pdb
• 関連するPDBエントリー: 4YQU 4YQV
• 分子名称: Glutathione S-transferase omega-1, 2-chloro-N-[4-chloro-3-(dimethylsulfamoyl)phenyl]acetamide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• 機能のキーワード: covalent inhibitor, thioltransferase, chloroacetamide, transferase-transferase inhibitor complex, transferase/transferase inhibitor
• 由来する生物種: Homo sapiens (Human)
• 細胞内の位置: Cytoplasm, cytosol : P78417
• タンパク質・核酸の鎖数: 3
• 化学式量合計: 85135.58

構造登録者

Stuckey, J.A. (登録日: 2015-03-13, 公開日: 2016-10-12, 最終更新日: 2024-10-16)

主引用文献

Ramkumar, K.,Samanta, S.,Kyani, A.,Yang, S.,Tamura, S.,Ziemke, E.,Stuckey, J.A.,Li, S.,Chinnaswamy, K.,Otake, H.,Debnath, B.,Yarovenko, V.,Sebolt-Leopold, J.S.,Ljungman, M.,Neamati, N.
Mechanistic evaluation and transcriptional signature of a glutathione S-transferase omega 1 inhibitor.
Nat Commun, 7:13084-13084, 2016

PubMed Abstract: Glutathione S-transferase omega 1 (GSTO1) is an atypical GST isoform that is overexpressed in several cancers and has been implicated in drug resistance. Currently, no small-molecule drug targeting GSTO1 is under clinical development. Here we show that silencing of GSTO1 with siRNA significantly impairs cancer cell viability, validating GSTO1 as a potential new target in oncology. We report on the development and characterization of a series of chloroacetamide-containing potent GSTO1 inhibitors. Co-crystal structures of GSTO1 with our inhibitors demonstrate covalent binding to the active site cysteine. These potent GSTO1 inhibitors suppress cancer cell growth, enhance the cytotoxic effects of cisplatin and inhibit tumour growth in colon cancer models as single agent. Bru-seq-based transcription profiling unravelled novel roles for GSTO1 in cholesterol metabolism, oxidative and endoplasmic stress responses, cytoskeleton and cell migration. Our findings demonstrate the therapeutic utility of GSTO1 inhibitors as anticancer agents and identify the novel cellular pathways under GSTO1 regulation in colorectal cancer.

PubMed: 27703239
DOI: 10.1038/ncomms13084

実験手法

X-RAY DIFFRACTION (2.38 Å)