4J70

Yeast 20S proteasome in complex with the belactosin derivative 3e

Summary for 4J70

• Entry DOI: 10.2210/pdb4j70/pdb
• Related: 1RYP 3E47 3TDD
• Related PRD ID: PRD_000915
• Descriptor: Proteasome component Y7, Proteasome component C11, Proteasome component PRE2, ... (16 entities in total)
• Functional Keywords: proteasome, drug discovery, irreversible inhibition, beta-lactone, ntn hydrolase, hydrolase-hydrolase inhibitor complex, 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: 28
• Total formula weight: 729671.38

Authors

Kawamura, S.,Unno, Y.,List, A.,Tanaka, M.,Sasaki, T.,Arisawa, M.,Asai, A.,Groll, M.,Shuto, S. (deposition date: 2013-02-12, release date: 2013-04-17, Last modification date: 2024-10-16)

Primary citation

Kawamura, S.,Unno, Y.,List, A.,Mizuno, A.,Tanaka, M.,Sasaki, T.,Arisawa, M.,Asai, A.,Groll, M.,Shuto, S.
Potent Proteasome Inhibitors Derived from the Unnatural cis-Cyclopropane Isomer of Belactosin A: Synthesis, Biological Activity, and Mode of Action.
J.Med.Chem., 56:3689-3700, 2013

PubMed Abstract: The natural product belactosin A (1) with a trans-cyclopropane structure is a useful prototype compound for developing potent proteasome (core particle, CP) inhibitors. To date, 1 and its analogues are the only CP ligands that bind to both the nonprimed S1 pocket as well as the primed substrate binding channel; however, these molecules harbor a high IC50 value of more than 1 μM. We have performed structure-activity relationship studies, thereby elucidating unnatural cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block the chymotrypsin-like active site of the human constitutive (cCP) and immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the yeast proteasome in complex with 3e revealed that the ligand is accommodated predominantly into the primed substrate binding channel and covalently binds to the active site threonine residue via its β-lactone ring-opening.

PubMed: 23547757
DOI: 10.1021/jm4002296

Experimental method

X-RAY DIFFRACTION (2.8 Å)