Sülzen Hagen, Fajtova Pavla, O'Donoghue Anthony J, Silhan Jan, Boura Evzen
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo namesti 2, 16610 Prague, Czech Republic.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA 92093, USA.
Molecules. 2025 Mar 20;30(6):1386. doi: 10.3390/molecules30061386.
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.
20S蛋白酶体是泛素-蛋白酶体系统的关键组成部分，在真核细胞中蛋白质降解调控方面发挥核心作用。马里佐米布（MZB），也称为盐孢霉素A，是一种源自[具体来源未提及]的天然γ-内酰胺-β-内酯化合物，是一种具有抗癌特性的强效20S蛋白酶体共价抑制剂。它对所有三种蛋白酶体亚基的广谱抑制作用以及穿越血脑屏障的能力，使其成为胶质母细胞瘤有前景的治疗候选药物。除此之外，MZB对原生动物寄生虫[具体名称未提及]的20S蛋白酶体（20S）也表现出显著抑制作用，表明其在寄生虫治疗方面的潜力。在此，我们展示了人20S蛋白酶体与MZB复合物在2.55 Å分辨率下的冷冻电镜结构。该结构揭示了MZB与20S蛋白酶体两个β环内所有六个催化亚基的结合模式，为其不可逆抑制机制提供了详细的分子理解。这些发现从分子水平上增强了MZB对癌症和寄生虫疾病的治疗潜力，并突出了海洋来源天然产物在靶向蛋白酶体用于治疗应用方面的作用。
