9HMN

CryoEM structure of human 20S proteasome in complex with proteasome inhibitor Salinosporamid A

Summary for 9HMN

• Entry DOI: 10.2210/pdb9hmn/pdb
• EMDB information: 52296
• Descriptor: Proteasome subunit alpha type-6, Proteasome subunit beta type-4, Proteasome subunit alpha type-7, ... (15 entities in total)
• Functional Keywords: inhibitor, 20s proteasome, salinosporamid a, hydrolase
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 28
• Total formula weight: 718640.15

Authors

Suelzen, H.,Boura, E.,Silhan, J. (deposition date: 2024-12-09, release date: 2025-03-05, Last modification date: 2025-07-02)

Primary citation

Sulzen, H.,Fajtova, P.,O'Donoghue, A.J.,Silhan, J.,Boura, E.
Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome.
Molecules, 30:-, 2025

PubMed Abstract: 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 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 (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.

PubMed: 40142161
DOI: 10.3390/molecules30061386

Experimental method

ELECTRON MICROSCOPY (2.55 Å)