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9hmn

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

Structural highlights

9hmn is a 20 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	Electron Microscopy, Resolution 2.55Å
Ligands:
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PSA2_HUMAN The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. The proteasome has an ATP-dependent proteolytic activity. PSMA2 may have a potential regulatory effect on another component(s) of the proteasome complex through tyrosine phosphorylation.

Publication Abstract from PubMed

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 gamma-lactam-beta-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 A resolution. This structure reveals the binding mode of MZB to all six catalytic subunits within the two beta-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.

Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome.,Sulzen H, Fajtova P, O'Donoghue AJ, Boura E, Silhan J bioRxiv [Preprint]. 2025 Jan 28:2025.01.28.635221. doi: , 10.1101/2025.01.28.635221. PMID:39974992^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Sülzen H, Fajtova P, O'Donoghue AJ, Boura E, Silhan J. Structural insights into Salinosporamide A mediated inhibition of the human 20S proteasome. bioRxiv [Preprint]. 2025 Jan 28:2025.01.28.635221. PMID:39974992 doi:10.1101/2025.01.28.635221