Xiuxiu Lu, Monika Chandravanshi, Venkata R Sabbasani, Snehal Gaikwad, V Keith Hughitt, Nana Gyabaah-Kessie, Bradley T Scroggins, Sudipto Das, Wazo Myint, Michelle E Clapp, Charles D Schwieters, Marzena A Dyba, Derek L Bolhuis, Janusz W Koscielniak, Thorkell Andresson, Michael J Emanuele, Nicholas G Brown, Hiroshi Matsuo, Raj Chari, Deborah E Citrin, Beverly A Mock, Rolf E Swenson, Kylie J Walters
Proteasome subunit hRpn13 is partially proteolyzed in certain cancer cell types to generate hRpn13Pru 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, hRpn13Pru is depleted in myeloma cells following treatment with XL44...
March 20, 2024: Nature Communications