| Structural highlights
Function
UBE2T_HUMAN Accepts ubiquitin from the E1 complex and catalyzes its covalent attachment to other proteins. Catalyzes monoubiquitination. Involved in mitomycin-C (MMC)-induced DNA repair: acts as a specific E2 ubiquitin-conjugating enzyme for the Fanconi anemia complex by associating with E3 ubiquitin-protein ligase FANCL and catalyzing monoubiquitination of FANCD2, a key step in the DNA damage pathway. Also mediates monoubiquitination of FANCL and FANCI. May contribute to ubiquitination and degradation of BRCA1. In vitro able to promote polyubiquitination using all 7 ubiquitin Lys residues, but may prefer 'Lys-11'-, 'Lys-27'-, 'Lys-48'- and 'Lys-63'-linked polyubiquitination.[1] [2] [3] [4] [5] [6]
Publication Abstract from PubMed
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.
Identification and characterization of inhibitors covalently modifying catalytic cysteine of UBE2T and blocking ubiquitin transfer.,Anantharajan J, Tan QW, Fulwood J, Sifang W, Huang Q, Ng HQ, Koh X, Xu W, Cherian J, Baburajendran N, Kang C, Ke Z Biochem Biophys Res Commun. 2023 Dec 31;689:149238. doi: , 10.1016/j.bbrc.2023.149238. Epub 2023 Nov 11. PMID:37979329[7]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Machida YJ, Machida Y, Chen Y, Gurtan AM, Kupfer GM, D'Andrea AD, Dutta A. UBE2T is the E2 in the Fanconi anemia pathway and undergoes negative autoregulation. Mol Cell. 2006 Aug;23(4):589-96. PMID:16916645 doi:http://dx.doi.org/10.1016/j.molcel.2006.06.024
- ↑ Alpi A, Langevin F, Mosedale G, Machida YJ, Dutta A, Patel KJ. UBE2T, the Fanconi anemia core complex, and FANCD2 are recruited independently to chromatin: a basis for the regulation of FANCD2 monoubiquitination. Mol Cell Biol. 2007 Dec;27(24):8421-30. Epub 2007 Oct 15. PMID:17938197 doi:http://dx.doi.org/10.1128/MCB.00504-07
- ↑ Alpi AF, Pace PE, Babu MM, Patel KJ. Mechanistic insight into site-restricted monoubiquitination of FANCD2 by Ube2t, FANCL, and FANCI. Mol Cell. 2008 Dec 26;32(6):767-77. doi: 10.1016/j.molcel.2008.12.003. PMID:19111657 doi:http://dx.doi.org/10.1016/j.molcel.2008.12.003
- ↑ Ueki T, Park JH, Nishidate T, Kijima K, Hirata K, Nakamura Y, Katagiri T. Ubiquitination and downregulation of BRCA1 by ubiquitin-conjugating enzyme E2T overexpression in human breast cancer cells. Cancer Res. 2009 Nov 15;69(22):8752-60. doi: 10.1158/0008-5472.CAN-09-1809. Epub , 2009 Nov 3. PMID:19887602 doi:http://dx.doi.org/10.1158/0008-5472.CAN-09-1809
- ↑ Longerich S, San Filippo J, Liu D, Sung P. FANCI binds branched DNA and is monoubiquitinated by UBE2T-FANCL. J Biol Chem. 2009 Aug 28;284(35):23182-6. doi: 10.1074/jbc.C109.038075. Epub 2009, Jul 8. PMID:19589784 doi:http://dx.doi.org/10.1074/jbc.C109.038075
- ↑ David Y, Ziv T, Admon A, Navon A. The E2 ubiquitin conjugating enzymes direct polyubiquitination to preferred lysines. J Biol Chem. 2010 Jan 8. PMID:20061386 doi:M109.089003
- ↑ Anantharajan J, Tan QW, Fulwood J, Sifang W, Huang Q, Ng HQ, 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. 2023 Dec 31;689:149238. PMID:37979329 doi:10.1016/j.bbrc.2023.149238
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