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)

Primary citation

Sulzen, H.,Fajtova, P.,O'Donoghue, A.J.,Boura, E.,Silhan, J.
Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome.
Biorxiv, 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), a natural γ-lactam-β-lactone compound derived from , 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.

PubMed: 39974992
DOI: 10.1101/2025.01.28.635221

Experimental method

ELECTRON MICROSCOPY (2.55 Å)