8cms | pdb_00008cms
OTUB2 in covalent complex with LN5P45
Structural highlights
FunctionOTUB2_HUMAN Hydrolase that can remove conjugated ubiquitin from proteins in vitro and may therefore play an important regulatory role at the level of protein turnover by preventing degradation. Mediates deubiquitination of both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains, with a preference for 'Lys-63'-linked polyubiquitin chains.[1] [2] Publication Abstract from PubMedUbiquitin thioesterase OTUB2, a cysteine protease from the ovarian tumor (OTU) deubiquitinase superfamily, is often overexpressed during tumor progression and metastasis. Development of OTUB2 inhibitors is therefore believed to be therapeutically important, yet potent and selective small-molecule inhibitors targeting OTUB2 are scarce. Here, we describe the development of an improved OTUB2 inhibitor, LN5P45, comprising a chloroacethydrazide moiety that covalently reacts to the active-site cysteine residue. LN5P45 shows outstanding target engagement and proteome-wide selectivity in living cells. Importantly, LN5P45 as well as other OTUB2 inhibitors strongly induce monoubiquitination of OTUB2 on lysine 31. We present a route to future OTUB2-related therapeutics and have shown that the OTUB2 inhibitor developed in this study can help to uncover new aspects of the related biology and open new questions regarding the understanding of OTUB2 regulation at the post-translational modification level. Cellular Validation of a Chemically Improved Inhibitor Identifies Monoubiquitination on OTUB2.,Gan J, de Vries J, Akkermans JJLL, Mohammed Y, Tjokrodirijo RTN, de Ru AH, Kim RQ, Vargas DA, Pol V, Fasan R, van Veelen PA, Neefjes J, van Dam H, Ovaa H, Sapmaz A, Geurink PP ACS Chem Biol. 2023 Sep 15;18(9):2003-2013. doi: 10.1021/acschembio.3c00227. Epub , 2023 Aug 29. PMID:37642399[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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