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PDBsum entry 2fak
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Contents |
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250 a.a.
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244 a.a.
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241 a.a.
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242 a.a.
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233 a.a.
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244 a.a.
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243 a.a.
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222 a.a.
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204 a.a.
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198 a.a.
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212 a.a.
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222 a.a.
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233 a.a.
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196 a.a.
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References listed in PDB file
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Key reference
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Title
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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.
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Authors
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M.Groll,
R.Huber,
B.C.Potts.
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Ref.
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J Am Chem Soc, 2006,
128,
5136-5141.
[DOI no: ]
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PubMed id
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Abstract
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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.
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