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6ML1

Structure of the USP15 deubiquitinase domain in complex with an affinity-matured inhibitory Ubv

Summary for 6ML1
Entry DOI10.2210/pdb6ml1/pdb
Related6CPM 6CRN
DescriptorUbiquitin carboxyl-terminal hydrolase 15,Ubiquitin carboxyl-terminal hydrolase 15,Ubiquitin carboxyl-terminal hydrolase 15, Ubiquitin variant 15.1a, Proteolyzed N-terminal tag of Ubv.15.1a construct, ... (10 entities in total)
Functional Keywordsdeubiuqitination, ubv, high-affinity, inhibition, signaling protein
Biological sourceHomo sapiens (Human)
More
Total number of polymer chains5
Total formula weight103802.90
Authors
Singer, A.U.,Teyra, J.,Boehmelt, G.,Lenter, M.,Sicheri, F.,Sidhu, S.S. (deposition date: 2018-09-26, release date: 2019-01-23, Last modification date: 2023-10-25)
Primary citationTeyra, 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
Cited by
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
PDB entries with the same primary citation
Experimental method
X-RAY DIFFRACTION (1.9 Å)
Structure validation

239803

数据于2025-08-06公开中

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