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PDBsum entry 4j70
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Hydrolase/hydrolase inhibitor
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PDB id
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4j70
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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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Potent proteasome inhibitors derived from the unnatural cis-Cyclopropane isomer of belactosin a: synthesis, Biological activity, And mode of action.
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Authors
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S.Kawamura,
Y.Unno,
A.List,
A.Mizuno,
M.Tanaka,
T.Sasaki,
M.Arisawa,
A.Asai,
M.Groll,
S.Shuto.
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Ref.
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J Med Chem, 2013,
56,
3689-3700.
[DOI no: ]
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PubMed id
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Abstract
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The natural product belactosin A (1) with a trans-cyclopropane structure is a
useful prototype compound for developing potent proteasome (core particle, CP)
inhibitors. To date, 1 and its analogues are the only CP ligands that bind to
both the nonprimed S1 pocket as well as the primed substrate binding channel;
however, these molecules harbor a high IC50 value of more than 1 μM. We have
performed structure-activity relationship studies, thereby elucidating unnatural
cis-cyclopropane derivatives of 1 that exhibit high potency to primarily block
the chymotrypsin-like active site of the human constitutive (cCP) and
immunoproteasome (iCP). The most active compound 3e reversibly inhibits cCP and
iCP similarly with an IC50 of 5.7 nM. X-ray crystallographic analysis of the
yeast proteasome in complex with 3e revealed that the ligand is accommodated
predominantly into the primed substrate binding channel and covalently binds to
the active site threonine residue via its β-lactone ring-opening.
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