6GOP

Yeast 20S Proteasome in complex with Homosalinosporamide A

Summary for 6GOP

• Entry DOI: 10.2210/pdb6gop/pdb
• Related: 2FAK 5CZ4
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 entities in total)
• Functional Keywords: hydrolase-hydrolase inhibitor complex, natural product, proteasome, inhibitor, binding analysis, hydrolase
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 28
• Total formula weight: 733341.63

Authors

Groll, M.,Romo, D. (deposition date: 2018-06-01, release date: 2018-08-01, Last modification date: 2024-11-13)

Primary citation

Groll, M.,Nguyen, H.,Vellalath, S.,Romo, D.
(-)-Homosalinosporamide A and Its Mode of Proteasome Inhibition: An X-ray Crystallographic Study.
Mar Drugs, 16:-, 2018

PubMed Abstract: Upon acylation of the proteasome by the β-lactone inhibitor salinosporamide A (SalA), tetrahydrofuran formation occurs by intramolecular alkylation of the incipient alkoxide onto the choroethyl sidechain and irreversibly blocks the active site. Our previously described synthetic approach to SalA, utilizing a bioinspired, late-stage, aldol-β-lactonization strategy to construct the bicyclic β-lactone core, enabled synthesis of (⁻)-homosalinosporamide A (homoSalA). This homolog was targeted to determine whether an intramolecular tetrahydropyran is formed in a similar manner to SalA. Herein, we report the X-ray structure of the yeast 20S proteasome:homoSalA-complex which reveals that tetrahydropyran ring formation does not occur despite comparable potency at the chymotrypsin-like active site in a luminogenic enzyme assay. Thus, the natural product derivative homoSalA blocks the proteasome by a covalent reversible mode of action, opening the door for further fine-tuning of proteasome inhibition.

PubMed: 30029468
DOI: 10.3390/md16070240

Experimental method

X-RAY DIFFRACTION (2.9 Å)