8JVL

Identification and characterization of inhibitors covalently modifying catalytic cysteine of UBE2T and blocking ubiquitin transfer

8JVL の概要

• エントリーDOI: 10.2210/pdb8jvl/pdb
• 分子名称: Ubiquitin-conjugating enzyme E2 T, 1-(4-methoxyphenyl)-1,2,3,4-tetrazole, 1,2-ETHANEDIOL, ... (4 entities in total)
• 機能のキーワード: ube2t, structure; drug discovery, covalent inhibitor, fanconi anemia, ligase-inhibitor complex, ligase/inhibitor
• 由来する生物種: Homo sapiens (human)
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 18068.84

構造登録者

Anantharajan, J.,Baburajendran, N. (登録日: 2023-06-28, 公開日: 2023-11-29)

主引用文献

Anantharajan, J.,Tan, Q.W.,Fulwood, J.,Sifang, W.,Huang, Q.,Ng, H.Q.,Koh, X.,Xu, W.,Cherian, J.,Baburajendran, N.,Kang, C.,Ke, Z.
Identification and characterization of inhibitors covalently modifying catalytic cysteine of UBE2T and blocking ubiquitin transfer.
Biochem.Biophys.Res.Commun., 689:149238-149238, 2023

PubMed Abstract: UBE2T is an E2 ubiquitin ligase critical for ubiquitination of substrate and plays important roles in many diseases. Despite the important function, UBE2T is considered as an undruggable target due to lack of a pocket for binding to small molecules with satisfied properties for clinical applications. To develop potent and specific UBE2T inhibitors, we adopted a high-throughput screening assay and two compounds-ETC-6152 and ETC-9004 containing a sulfone tetrazole scaffold were identified. Solution NMR study demonstrated the direct interactions between UBE2T and compounds in solution. Further co-crystal structures reveal the binding modes of these compounds. Both compound hydrolysation and formation of a hydrogen bond with the thiol group of the catalytic cysteine were observed. The formation of covalent complex was confirmed with mass spectrometry. As these two compounds inhibit ubiquitin transfer, our study provides a strategy to develop potent inhibitors of UBE2T.

PubMed: 37979329
DOI: 10.1016/j.bbrc.2023.149238

実験手法

X-RAY DIFFRACTION (2.06 Å)