8ftq
Crystal structure of hRpn13 Pru domain in complex with Ubiquitin and XL44
Structural highlights
FunctionADRM1_HUMAN Functions as a proteasomal ubiquitin receptor. Recruits the deubiquitinating enzyme UCHL5 at the 26S proteasome and promotes its activity.[1] [2] [3] [4] [5] Publication Abstract from PubMedProteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13(Pru) by degradation of its UCHL5/Uch37-binding DEUBAD domain and retention of an intact proteasome- and ubiquitin-binding Pru domain. By using structure-guided virtual screening, we identify an hRpn13 binder (XL44) and solve its structure ligated to hRpn13 Pru by integrated X-ray crystallography and NMR to reveal its targeting mechanism. Surprisingly, hRpn13(Pru) is depleted in myeloma cells following treatment with XL44. TMT-MS experiments reveal a select group of off-targets, including PCNA clamp-associated factor PCLAF and ribonucleoside-diphosphate reductase subunit M2 (RRM2), that are similarly depleted by XL44 treatment. XL44 induces hRpn13-dependent apoptosis and also restricts cell viability by a PCLAF-dependent mechanism. A KEN box, but not ubiquitination, is required for XL44-induced depletion of PCLAF. Here, we show that XL44 induces ubiquitin-dependent loss of hRpn13(Pru) and ubiquitin-independent loss of select KEN box containing proteins. A structure-based designed small molecule depletes hRpn13(Pru) and a select group of KEN box proteins.,Lu X, Chandravanshi M, Sabbasani VR, Gaikwad S, Hughitt VK, Gyabaah-Kessie N, Scroggins BT, Das S, Myint W, Clapp ME, Schwieters CD, Dyba MA, Bolhuis DL, Koscielniak JW, Andresson T, Emanuele MJ, Brown NG, Matsuo H, Chari R, Citrin DE, Mock BA, Swenson RE, Walters KJ Nat Commun. 2024 Mar 20;15(1):2485. doi: 10.1038/s41467-024-46644-7. PMID:38509117[6] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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