A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins
© 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply..
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. 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 hRpn13Pru and ubiquitin-independent loss of select KEN box containing proteins.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:15 |
|---|---|
| Enthalten in: |
Nature communications - 15(2024), 1 vom: 20. März, Seite 2485 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Lu, Xiuxiu [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
EC 3.4.25.1 |
|---|
| Anmerkungen: |
Date Completed 22.03.2024 Date Revised 30.03.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1038/s41467-024-46644-7 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM369987012 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM369987012 | ||
| 003 | DE-627 | ||
| 005 | 20240331001206.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240322s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1038/s41467-024-46644-7 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1357.xml |
| 035 | |a (DE-627)NLM369987012 | ||
| 035 | |a (NLM)38509117 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Lu, Xiuxiu |e verfasserin |4 aut | |
| 245 | 1 | 2 | |a A structure-based designed small molecule depletes hRpn13Pru and a select group of KEN box proteins |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 22.03.2024 | ||
| 500 | |a Date Revised 30.03.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply. | ||
| 520 | |a 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. 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 hRpn13Pru and ubiquitin-independent loss of select KEN box containing proteins | ||
| 650 | 4 | |a Journal Article | |
| 650 | 7 | |a Proteasome Endopeptidase Complex |2 NLM | |
| 650 | 7 | |a EC 3.4.25.1 |2 NLM | |
| 650 | 7 | |a Membrane Glycoproteins |2 NLM | |
| 650 | 7 | |a Intracellular Signaling Peptides and Proteins |2 NLM | |
| 650 | 7 | |a Ubiquitin |2 NLM | |
| 650 | 7 | |a Transcription Factors |2 NLM | |
| 700 | 1 | |a Chandravanshi, Monika |e verfasserin |4 aut | |
| 700 | 1 | |a Sabbasani, Venkata R |e verfasserin |4 aut | |
| 700 | 1 | |a Gaikwad, Snehal |e verfasserin |4 aut | |
| 700 | 1 | |a Hughitt, V Keith |e verfasserin |4 aut | |
| 700 | 1 | |a Gyabaah-Kessie, Nana |e verfasserin |4 aut | |
| 700 | 1 | |a Scroggins, Bradley T |e verfasserin |4 aut | |
| 700 | 1 | |a Das, Sudipto |e verfasserin |4 aut | |
| 700 | 1 | |a Myint, Wazo |e verfasserin |4 aut | |
| 700 | 1 | |a Clapp, Michelle E |e verfasserin |4 aut | |
| 700 | 1 | |a Schwieters, Charles D |e verfasserin |4 aut | |
| 700 | 1 | |a Dyba, Marzena A |e verfasserin |4 aut | |
| 700 | 1 | |a Bolhuis, Derek L |e verfasserin |4 aut | |
| 700 | 1 | |a Koscielniak, Janusz W |e verfasserin |4 aut | |
| 700 | 1 | |a Andresson, Thorkell |e verfasserin |4 aut | |
| 700 | 1 | |a Emanuele, Michael J |e verfasserin |4 aut | |
| 700 | 1 | |a Brown, Nicholas G |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuo, Hiroshi |e verfasserin |4 aut | |
| 700 | 1 | |a Chari, Raj |e verfasserin |4 aut | |
| 700 | 1 | |a Citrin, Deborah E |e verfasserin |4 aut | |
| 700 | 1 | |a Mock, Beverly A |e verfasserin |4 aut | |
| 700 | 1 | |a Swenson, Rolf E |e verfasserin |4 aut | |
| 700 | 1 | |a Walters, Kylie J |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Nature communications |d 2010 |g 15(2024), 1 vom: 20. März, Seite 2485 |w (DE-627)NLM199274525 |x 2041-1723 |7 nnns |
| 773 | 1 | 8 | |g volume:15 |g year:2024 |g number:1 |g day:20 |g month:03 |g pages:2485 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1038/s41467-024-46644-7 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 15 |j 2024 |e 1 |b 20 |c 03 |h 2485 | ||