6G7F

Yeast 20S proteasome in complex with Cystargolide B

Summary for 6G7F

• Entry DOI: 10.2210/pdb6g7f/pdb
• Descriptor: Proteasome subunit alpha type-2, Proteasome subunit beta type-4, Proteasome subunit beta type-5, ... (18 entities in total)
• Functional Keywords: proteasome, inhibitor, beta lactone; natural product, binding analysis, hydrolase
• Biological source: Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast); More
• Total number of polymer chains: 28
• Total formula weight: 733562.69

Authors

Groll, M.,Tello-Aburto, R. (deposition date: 2018-04-05, release date: 2018-09-12, Last modification date: 2024-01-17)

Primary citation

Niroula, D.,Hallada, L.P.,Le Chapelain, C.,Ganegamage, S.K.,Dotson, D.,Rogelj, S.,Groll, M.,Tello-Aburto, R.
Design, synthesis, and evaluation of cystargolide-based beta-lactones as potent proteasome inhibitors.
Eur J Med Chem, 157:962-977, 2018

PubMed Abstract: The peptidic β-lactone proteasome inhibitors (PIs) cystargolides A and B were used to conduct structure-activity relationship (SAR) studies in order to assess their anticancer potential. A total of 24 different analogs were designed, synthesized and evaluated for proteasome inhibition, for cytotoxicity towards several cancer cell lines, and for their ability to enter intact cells. X-ray crystallographic analysis and subunit selectivity was used to determine the specific subunit binding associated with the structural modification of the β-lactone (P), peptidic core, (P and P), and end-cap (P) of our scaffold. The cystargolide derivative 5k, structurally unique at both P and P, exhibited the most promising inhibitory activity for the β5 subunit of human proteasomes (IC = 3.1 nM) and significant cytotoxicity towards MCF-7 (IC = 416 nM), MDA-MB-231 (IC = 74 nM) and RPMI 8226 (IC = 41 nM) cancer cell lines. Cellular infiltration assays revealed that minor structural modifications have significant effects on the ability of our PIs to inhibit intracellular proteasomes, and we identified 5k as a promising candidate for continued therapeutic studies. Our novel drug lead 5k is a more potent proteasome inhibitor than carfilzomib with mid-to-low nanomolar IC measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.

PubMed: 30165344
DOI: 10.1016/j.ejmech.2018.08.052

Experimental method

X-RAY DIFFRACTION (2.7 Å)