3GPJ

Crystal structure of the yeast 20S proteasome in complex with syringolin B

Summary for 3GPJ

• Entry DOI: 10.2210/pdb3gpj/pdb
• Related: 1ryp 2ZCY 3BDM 3GPT 3GPW
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: proteasome, virulence, ubiquitin, cancer therapy, immunology, cytoplasm, hydrolase, nucleus, phosphoprotein, protease, threonine protease, isopeptide bond, ubl conjugation, zymogen
• Biological source: Saccharomyces cerevisiae (yeast); More
• Cellular location: Cytoplasm: P23639 P22141 P30656 P23724 P30657 P38624 P23638 P40303 P32379 P40302 P21242 P21243 P25043 P25451
• Total number of polymer chains: 28
• Total formula weight: 706188.69

Authors

Groll, M.,Huber, R.,Kaiser, M. (deposition date: 2009-03-23, release date: 2009-06-02, Last modification date: 2024-10-16)

Primary citation

Clerc, J.,Groll, M.,Illich, D.J.,Bachmann, A.S.,Huber, R.,Schellenberg, B.,Dudler, R.,Kaiser, M.
Synthetic and structural studies on syringolin A and B reveal critical determinants of selectivity and potency of proteasome inhibition
Proc.Natl.Acad.Sci.USA, 106:6507-6512, 2009

PubMed Abstract: Syrbactins, a family of natural products belonging either to the syringolin or glidobactin class, are highly potent proteasome inhibitors. Although sharing similar structural features, they differ in their macrocyclic lactam core structure and exocyclic side chain. These structural variations critically influence inhibitory potency and proteasome subsite selectivity. Here, we describe the total synthesis of syringolin A and B, which together with enzyme kinetic and structural studies, allowed us to elucidate the structural determinants underlying the proteasomal subsite selectivity and binding affinity of syrbactins. These findings were used successfully in the rational design and synthesis of a syringolin A-based lipophilic derivative, which proved to be the most potent syrbactin-based proteasome inhibitor described so far. With a K(i)' of 8.65 +/- 1.13 nM for the chymotryptic activity, this syringolin A derivative displays a 100-fold higher potency than the parent compound syringolin A. In light of the medicinal relevance of proteasome inhibitors as anticancer compounds, the present findings may assist in the rational design and development of syrbactin-based chemotherapeutics.

PubMed: 19359491
DOI: 10.1073/pnas.0901982106

Experimental method

X-RAY DIFFRACTION (2.7 Å)