Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388963%3A_____%2F25%3A00618755" target="_blank" >RIV/61388963:_____/25:00618755 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216224:90127/25:00143937

Výsledek na webu

<a href="https://doi.org/10.3390/molecules30061386" target="_blank" >https://doi.org/10.3390/molecules30061386</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.3390/molecules30061386" target="_blank" >10.3390/molecules30061386</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome

Popis výsledku v původním jazyce

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 gamma-lactam-beta-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 & Aring, 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 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.

Název v anglickém jazyce

Structural Insights into Salinosporamide a Mediated Inhibition of the Human 20S Proteasome

Popis výsledku anglicky

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 gamma-lactam-beta-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 & Aring, 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 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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10608 - Biochemistry and molecular biology

Projekt

<a href="/cs/project/LX22NPO5103" target="_blank" >LX22NPO5103: Národní institut virologie a bakteriologie</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Molecules

ISSN

1420-3049

e-ISSN

1420-3049

Svazek periodika

30

Číslo periodika v rámci svazku

6

Stát vydavatele periodika

CH - Švýcarská konfederace

Počet stran výsledku

12

Strana od-do

1386

Kód UT WoS článku

001452896100001

EID výsledku v databázi Scopus

2-s2.0-105001140522