2fak: Difference between revisions

Revision as of 03:39, 4 May 2008

Crystal structure of Salinosporamide A in complex with the yeast 20S proteasome

OverviewOverview

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 angstroms resolution. Each ligand is covalently bound to Thr1O(gamma) via an ester linkage to the carbonyl derived from the beta-lactone ring of the inhibitor. In the case of 1, nucleophilic addition to the beta-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 beta-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.

About this StructureAbout this Structure

2FAK is a Protein complex structure of sequences from Saccharomyces cerevisiae. Full crystallographic information is available from OCA.

ReferenceReference

Crystal structures of Salinosporamide A (NPI-0052) and B (NPI-0047) in complex with the 20S proteasome reveal important consequences of beta-lactone ring opening and a mechanism for irreversible binding., Groll M, Huber R, Potts BC, J Am Chem Soc. 2006 Apr 19;128(15):5136-41. PMID:16608349 Page seeded by OCA on Sun May 4 03:39:50 2008

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OCA

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 [[Image:2fak.gif|left|200px]]
- {{Structure
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-}}
 '''Crystal structure of Salinosporamide A in complex with the yeast 20S proteasome'''
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 [[Category: Groll, M.]]
 [[Category: Potts, B C.]]
-[[Category: drug design]]
+[[Category: Drug design]]
-[[Category: inhibitor]]
+[[Category: Inhibitor]]
-[[Category: protease]]
+[[Category: Protease]]
-[[Category: proteasome]]
+[[Category: Proteasome]]
-[[Category: ubiquitin]]
+[[Category: Ubiquitin]]
+''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Sun May  4 03:39:50 2008''
-''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Mon Mar 31 03:00:06 2008''