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 Salinispora tropica 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 Trichomonas vaginalis (Tv20S), 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.

• Keywords
• 20S, MZB, cryo-EM, marizomib, proteasome,
• MeSH
• Cryoelectron Microscopy MeSH
• Proteasome Inhibitors * chemistry   pharmacology   MeSH
• Lactones * chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Proteasome Endopeptidase Complex * chemistry   metabolism   MeSH
• Pyrroles * chemistry   pharmacology   MeSH
• Protein Binding MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Proteasome Inhibitors * MeSH
• Lactones * MeSH
• marizomib MeSH Browser
• Proteasome Endopeptidase Complex * MeSH
• Pyrroles * MeSH

The 20S proteasome, a critical component of the ubiquitin-proteasome system, plays a central role in regulating protein degradation in eukaryotic cells. Marizomib (MZB), a natural γ-lactam-β-lactone compound derived from Salinispora tropica, is a potent 20S proteasome covalent inhibitor with demonstrated anticancer properties. Its broad-spectrum inhibition of all three proteasome subunits and ability to cross the blood-brain barrier has made it a promising therapeutic candidate for glioblastoma. 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 explain the therapeutic potential of MZB at the molecular level and highlight marine-derived natural products in targeting the proteasome for anticancer treatment.

• Publication type
• Journal Article MeSH
• Preprint MeSH