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PDBsum entry 3d29
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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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Proteasome inhibition by fellutamide b induces nerve growth factor synthesis.
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Authors
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J.Hines,
M.Groll,
M.Fahnestock,
C.M.Crews.
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Ref.
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Chem Biol, 2008,
15,
501-512.
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PubMed id
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Abstract
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Neurotrophic small molecules have the potential to aid in the treatment of
neuronal injury and neurodegenerative diseases. The natural product fellutamide
B, originally isolated from Penicillium fellutanum, potently induces nerve
growth factor (NGF) release from fibroblasts and glial-derived cells, although
the mechanism for this neurotrophic activity has not been elucidated. Here, we
report that fellutamide B potently inhibits proteasome catalytic activity.
High-resolution structural information obtained from cocrystallization of the
20S proteasome reveals novel aspects regarding beta-subunit binding and adduct
formation by fellutamide B to inhibit their hydrolytic activity. We demonstrate
that fellutamide B and other proteasome inhibitors increased NGF gene
transcription via a cis-acting element (or elements) in the promoter. These
results demonstrate an unrecognized connection between proteasome inhibition and
NGF production, suggesting a possible new strategy in the development of
neurotrophic agents.
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