4GK7

yeast 20S proteasome in complex with the Syringolin-Glidobactin chimera

Summary for 4GK7

• Entry DOI: 10.2210/pdb4gk7/pdb
• Related: 1RYP 2ZCY 3BDM
• Related PRD ID: PRD_001047
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: proteasome, cancer, protein degradation, inhibition, natural product derivative, ntn-hydrolase, hydrolase-hydrolase inhibitor complex, 12-membered dipeptide-macrolactam, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 34
• Total formula weight: 707510.63

Authors

Groll, M.,Stein, M.L.,Bachmann, A. (deposition date: 2012-08-10, release date: 2012-08-29, Last modification date: 2023-11-15)

Primary citation

Archer, C.R.,Groll, M.,Stein, M.L.,Schellenberg, B.,Clerc, J.,Kaiser, M.,Kondratyuk, T.P.,Pezzuto, J.M.,Dudler, R.,Bachmann, A.S.
Activity enhancement of the synthetic syrbactin proteasome inhibitor hybrid and biological evaluation in tumor cells.
Biochemistry, 51:6880-6888, 2012

PubMed Abstract: Syrbactins belong to a recently emergent class of bacterial natural product inhibitors that irreversibly inhibit the proteasome of eukaryotes by a novel mechanism. The total syntheses of the syrbactin molecules syringolin A, syringolin B, and glidobactin A have been achieved, which allowed the preparation of syrbactin-inspired derivatives, such as the syringolin A-glidobactin A hybrid molecule (SylA-GlbA). To determine the potency of SylA-GlbA, we employed both in vitro and cell culture-based proteasome assays that measure the subcatalytic chymotrypsin-like (CT-L), trypsin-like (T-L), and caspase-like (C-L) activities. We further studied the inhibitory effects of SylA-GlbA on tumor cell growth using a panel of multiple myeloma, neuroblastoma, and ovarian cancer cell lines and showed that SylA-GlbA strongly blocks the activity of NF-κB. To gain more insights into the structure-activity relationship, we cocrystallized SylA-GlbA in complex with the proteasome and determined the X-ray structure. The electron density map displays covalent binding of the Thr1O(γ) atoms of all active sites to the macrolactam ring of the ligand via ether bond formation, thus providing insights into the structure-activity relationship for the improved affinity of SylA-GlbA for the CT-L activity compared to those of the natural compounds SylA and GlbA. Our study revealed that the novel synthetic syrbactin compound represents one of the most potent proteasome inhibitors analyzed to date and therefore exhibits promising properties for improved drug development as an anticancer therapeutic.

PubMed: 22870914
DOI: 10.1021/bi300841r

Experimental method

X-RAY DIFFRACTION (2.8 Å)