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PDBsum entry 3gpt
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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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Snapshots of the fluorosalinosporamide/20s complex offer mechanistic insights for fine tuning proteasome inhibition.
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Authors
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M.Groll,
K.A.Mcarthur,
V.R.Macherla,
R.R.Manam,
B.C.Potts.
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Ref.
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J Med Chem, 2009,
52,
5420-5428.
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PubMed id
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Abstract
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Many marketed drugs contain fluorine, reflecting its ability to modulate a
variety of biological responses. The unique 20S proteasome inhibition profile of
fluorosalinosporamide compared to chlorinated anticancer agent salinosporamide A
(NPI-0052) is exemplary and relates to each halogen's leaving group potential.
Crystal structures of fluoro-, hydroxy-, and bromosalinosporamide in complex
with the yeast 20S proteasome core particle (CP) provide mechanistic insights
into ligand binding and leaving group elimination and the ability to fine-tune
the duration of proteasome inhibition. Fluorosalinosporamide/CP crystal
structures determined over time offer striking snapshots of the ligand trapped
with an intact fluoroethyl group in anticipation of fluoride elimination,
followed by complete nucleophilic displacement of fluoride to give the highly
stabilized cyclic ether found for salinosporamide A and bromosalinosporamide.
This two-step reaction pathway is consistent with a mechanism for partially
reversible proteasome inhibition by fluorosalinosporamide. Proteasome catalyzed
fluoride displacement provides preliminary insights into the active site Thr1N
pK(a).
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