6g8n

From Proteopedia

Yeast 20S proteasome in complex with Cystargolide B Derivative 2

Structural highlights

6g8n is a 20 chain structure with sequence from Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 3Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

PSA2_YEAST The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that 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. It has an ATP-dependent proteolytic activity.

Publication Abstract from PubMed

The peptidic beta-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 beta-lactone (P1), peptidic core, (Px and Py), and end-cap (Pz) of our scaffold. The cystargolide derivative 5k, structurally unique at both Py and P1, exhibited the most promising inhibitory activity for the beta5 subunit of human proteasomes (IC50=3.1nM) and significant cytotoxicity towards MCF-7 (IC50=416nM), MDA-MB-231 (IC50=74nM) and RPMI 8226 (IC50=41nM) 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 IC50 measurements and it is cytotoxic against multiple cancer cell lines at levels approaching those of carfilzomib.

Design, synthesis, and evaluation of cystargolide-based beta-lactones as potent proteasome inhibitors.,Niroula D, Hallada LP, Le Chapelain C, Ganegamage SK, Dotson D, Rogelj S, Groll M, Tello-Aburto R Eur J Med Chem. 2018 Aug 20;157:962-977. doi: 10.1016/j.ejmech.2018.08.052. PMID:30165344^[1]

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

References

↑ Niroula D, Hallada LP, Le Chapelain C, Ganegamage SK, 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. 2018 Aug 20;157:962-977. doi: 10.1016/j.ejmech.2018.08.052. PMID:30165344 doi:http://dx.doi.org/10.1016/j.ejmech.2018.08.052