Crystal Structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in Complex with the 20S Proteasome Reveal Important Consequences of β-Lactone Ring Opening and a Mechanism for Irreversible Binding

• Published in: Journal of the American Chemical Society Vol. 128; no. 15; pp. 5136 - 5141
• Main Authors: Groll, Michael, Huber, Robert, Potts, Barbara C. M
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 19.04.2006
• ISSN: 0002-7863; 1520-5126
• DOI: 10.1021/ja058320b

The crystal structures of the yeast 20S proteasome core particle (CP) in complex with Salinosporamides A (NPI-0052; 1) and B (4) were solved at <3 Å resolution. Each ligand is covalently bound to Thr1Oγ via an ester linkage to the carbonyl derived from the β-lactone ring of the inhibitor. In the case of 1, nucleophilic addition to the β-lactone ring is followed by addition of C-3O to the chloroethyl group, giving rise to a cyclic ether. The crystal structures were compared to that of the omuralide/CP structure solved previously, and the collective data provide new insights into the mechanism of inhibition and irreversible binding of 1. Upon opening of the β-lactone ring, C-3O assumes the position occupied by a water molecule in the unligated enzyme and hinders deacylation of the enzyme−ligand complex. Furthermore, the resulting protonation state of Thr1NH2 deactivates the catalytic N-terminus.