Human ubiquitin specific peptidase 5, second ZnF domain, in complex with inhibitor DAT180

USP5 is a ubiquitin-specific cysteine protease which disassembles unanchored polyubiquitin chains to recycle free mono-ubiquitin¹.  USP5 is an 835 amino acid protein that has been associated with tumorigenesis^2–6, neurodegeneration^7–9, viral infections^10,11, DNA damage repair¹² and stress granules¹³. The domain architecture of USP5 consists of a zinc finger ubiquitin-binding domain (ZnF-UBD) spanning residues 173-283, a functional catalytic domain, two ubiquitin associated domains (UBA), and a cryptic zinc finger ubiquitin-binding domain (nUBP)¹⁴. The ZnF-UBD recognizes the C-terminal di-glycine motif of ubiquitin and has been associated with allosteric modulation of USP5 activity^1,15,16 and alternatively with substrate recognition and positioning¹⁴. This co-crystal structure is one of the first of the USP5 ZnF-UBD with a ligand bound in the ubiquitin-binding pocket.

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(11)     Ovaa, H.; Kessler, B. M.; Rolen, U.; Galardy, P. J.; Ploegh, H. L.; Masucci, M. G. Activity-Based Ubiquitin-Specific Protease (USP) Profiling of Virus-Infected and Malignant Human Cells. Proc. Natl. Acad. Sci. 2004. https://doi.org/10.1073/pnas.0308411100.

(12)     Nakajima, S.; Lan, L.; Wei, L.; Hsieh, C. L.; Rapić-Otrin, V.; Yasui, A.; Levine, A. S. Ubiquitin-Specific Protease 5 Is Required for the Efficient Repair of DNA Double-Strand Breaks. PLoS One 2014. https://doi.org/10.1371/journal.pone.0084899.

(13)     Xie, X.; Matsumoto, S.; Endo, A.; Fukushima, T.; Kawahara, H.; Saeki, Y.; Komada, M. Deubiquitylases USP5 and USP13 Are Recruited to and Regulate Heat-Induced Stress Granules through Their Deubiquitylating Activities. J. Cell Sci. 2018. https://doi.org/10.1242/jcs.210856.

(14)     Avvakumov, G. V.; Walker, J. R.; Xue, S.; Allali-Hassani, A.; Asinas, A.; Nair, U. B.; Fang, X.; Zuo, X.; Wang, Y. X.; Wilkinson, K. D.; et al. Two ZnF-UBP Domains in Isopeptidase T (USP5). Biochemistry 2012. https://doi.org/10.1021/bi200854q.

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(16)     Dang, L. C.; Melandri, F. D.; Stein, R. L. Kinetic and Mechanistic Studies on the Hydrolysis of Ubiquitin C- Terminal 7-Amido-4-Methylcoumarin by Deubiquitinating Enzymes. Biochemistry 1998. https://doi.org/10.1021/bi9723360.