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

Groll, Michael, Huber, Robert and Potts, Barbara C. M. 2006. 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. Journal of the American Chemical Society 128 (15) , pp. 5136-5141. 10.1021/ja058320b

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Abstract

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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	American Chemical Society
ISSN:	0002-7863
Last Modified:	24 Jun 2017 11:00
URI:	https://orca.cardiff.ac.uk/id/eprint/69996

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