Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome
The 20S proteasome, a critical component of the ubiquitin–proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), also known as salinosporamide A, is a natural γ-lactam-β-lactone compound derived from <i>Salinispora tropica</i> and...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2025-03-01
|
| Series: | Molecules |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1420-3049/30/6/1386 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849342665460547584 |
|---|---|
| author | Hagen Sülzen Pavla Fajtova Anthony J. O’Donoghue Jan Silhan Evzen Boura |
| author_facet | Hagen Sülzen Pavla Fajtova Anthony J. O’Donoghue Jan Silhan Evzen Boura |
| author_sort | Hagen Sülzen |
| collection | DOAJ |
| description | The 20S proteasome, a critical component of the ubiquitin–proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), also known as salinosporamide A, is a natural γ-lactam-β-lactone compound derived from <i>Salinispora tropica</i> and is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and its ability to cross the blood–brain barrier has made it a promising therapeutic candidate for glioblastoma. In addition to this, MZB also demonstrates significant inhibition against the 20S proteasome of <i>Trichomonas vaginalis</i> (<i>Tv</i>20S), a protozoan parasite, suggesting its potential for parasitic treatments. Here, we present the cryo-EM structure of the human 20S proteasome in complex with MZB at 2.55 Å resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings enhance the therapeutic potential of MZB for both cancer and parasitic diseases at the molecular level and highlight marine-derived natural products in targeting the proteasome for therapeutic applications. |
| format | Article |
| id | doaj-art-2a14da5f862c419ca260d09dc2b1beca |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-2a14da5f862c419ca260d09dc2b1beca2025-08-20T03:43:20ZengMDPI AGMolecules1420-30492025-03-01306138610.3390/molecules30061386Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S ProteasomeHagen Sülzen0Pavla Fajtova1Anthony J. O’Donoghue2Jan Silhan3Evzen Boura4Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech RepublicInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech RepublicSkaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USAInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech RepublicInstitute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech RepublicThe 20S proteasome, a critical component of the ubiquitin–proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), also known as salinosporamide A, is a natural γ-lactam-β-lactone compound derived from <i>Salinispora tropica</i> and is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and its ability to cross the blood–brain barrier has made it a promising therapeutic candidate for glioblastoma. In addition to this, MZB also demonstrates significant inhibition against the 20S proteasome of <i>Trichomonas vaginalis</i> (<i>Tv</i>20S), a protozoan parasite, suggesting its potential for parasitic treatments. Here, we present the cryo-EM structure of the human 20S proteasome in complex with MZB at 2.55 Å resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two β-rings of the 20S proteasome, providing a detailed molecular understanding of its irreversible inhibitory mechanism. These findings enhance the therapeutic potential of MZB for both cancer and parasitic diseases at the molecular level and highlight marine-derived natural products in targeting the proteasome for therapeutic applications.https://www.mdpi.com/1420-3049/30/6/138620SproteasomemarizomibMZBcryo-EM |
| spellingShingle | Hagen Sülzen Pavla Fajtova Anthony J. O’Donoghue Jan Silhan Evzen Boura Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome Molecules 20S proteasome marizomib MZB cryo-EM |
| title | Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome |
| title_full | Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome |
| title_fullStr | Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome |
| title_full_unstemmed | Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome |
| title_short | Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome |
| title_sort | structural insights into salinosporamide a mediated inhibition of the human 20s proteasome |
| topic | 20S proteasome marizomib MZB cryo-EM |
| url | https://www.mdpi.com/1420-3049/30/6/1386 |
| work_keys_str_mv | AT hagensulzen structuralinsightsintosalinosporamideamediatedinhibitionofthehuman20sproteasome AT pavlafajtova structuralinsightsintosalinosporamideamediatedinhibitionofthehuman20sproteasome AT anthonyjodonoghue structuralinsightsintosalinosporamideamediatedinhibitionofthehuman20sproteasome AT jansilhan structuralinsightsintosalinosporamideamediatedinhibitionofthehuman20sproteasome AT evzenboura structuralinsightsintosalinosporamideamediatedinhibitionofthehuman20sproteasome |