8JVL

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

Summary for 8JVL

• Entry DOI: 10.2210/pdb8jvl/pdb
• Descriptor: Ubiquitin-conjugating enzyme E2 T, 1-(4-methoxyphenyl)-1,2,3,4-tetrazole, 1,2-ETHANEDIOL, ... (4 entities in total)
• Functional Keywords: ube2t, structure; drug discovery, covalent inhibitor, fanconi anemia, ligase-inhibitor complex, ligase/inhibitor
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 18068.84

Authors

Anantharajan, J.,Baburajendran, N. (deposition date: 2023-06-28, release date: 2023-11-29)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.06 Å)