6CPM

Structure of the USP15 deubiquitinase domain in complex with a third-generation inhibitory Ubv

Summary for 6CPM

• Entry DOI: 10.2210/pdb6cpm/pdb
• Related: 6CRN 6CSI
• Descriptor: Ubiquitin carboxyl-terminal hydrolase 15, Ubiquitin variant 15.1d, CALCIUM ION, ... (8 entities in total)
• Functional Keywords: deubiuqitination, ubv, high-affinity, inhibition, signaling protein
• Biological source: Homo sapiens (Human); More
• Total number of polymer chains: 4
• Total formula weight: 99524.44

Authors

Singer, A.U.,Teyra, J.,Boehmelt, G.,Lenter, M.,Sicheri, F.,Sidhu, S.S. (deposition date: 2018-03-13, release date: 2019-01-23, Last modification date: 2024-04-03)

Primary citation

Teyra, J.,Singer, A.U.,Schmitges, F.W.,Jaynes, P.,Kit Leng Lui, S.,Polyak, M.J.,Fodil, N.,Krieger, J.R.,Tong, J.,Schwerdtfeger, C.,Brasher, B.B.,Ceccarelli, D.F.J.,Moffat, J.,Sicheri, F.,Moran, M.F.,Gros, P.,Eichhorn, P.J.A.,Lenter, M.,Boehmelt, G.,Sidhu, S.S.
Structural and Functional Characterization of Ubiquitin Variant Inhibitors of USP15.
Structure, 27:590-, 2019

PubMed Abstract: The multi-domain deubiquitinase USP15 regulates diverse eukaryotic processes and has been implicated in numerous diseases. We developed ubiquitin variants (UbVs) that targeted either the catalytic domain or each of three adaptor domains in USP15, including the N-terminal DUSP domain. We also designed a linear dimer (diUbV), which targeted the DUSP and catalytic domains, and exhibited enhanced specificity and more potent inhibition of catalytic activity than either UbV alone. In cells, the UbVs inhibited the deubiquitination of two USP15 substrates, SMURF2 and TRIM25, and the diUbV inhibited the effects of USP15 on the transforming growth factor β pathway. Structural analyses revealed that three distinct UbVs bound to the catalytic domain and locked the active site in a closed, inactive conformation, and one UbV formed an unusual strand-swapped dimer and bound two DUSP domains simultaneously. These inhibitors will enable the study of USP15 function in oncology, neurology, immunology, and inflammation.

PubMed: 30713027
DOI: 10.1016/j.str.2019.01.002

Experimental method

X-RAY DIFFRACTION (2.011 Å)