3D29

Proteasome Inhibition by Fellutamide B

Summary for 3D29

• Entry DOI: 10.2210/pdb3d29/pdb
• Related: 1ryp
• Descriptor: PRE8 isoform 1, Proteasome subunit beta, proteasome endopeptidase complex, ... (17 entities in total)
• Functional Keywords: anti-parallel beta-sheet structure flanked by alpha-helices, cytoplasm, hydrolase, nucleus, protease, proteasome, threonine protease, ubl conjugation, phosphoprotein, zymogen
• Biological source: Saccharomyces cerevisiae (brewer's yeast); More
• Cellular location: Cytoplasm: A0A6L1BIF8 A0A6A5Q0W2 A0A6A5Q5W3 A0A6A5Q0P3 A0A8H8ULD3 P38624 A0A6A5PXC6 A0A6A5Q273 A0A6A5PXN2 A0A6A5PTH4 A0A6A5Q4M4 A0A6A5PYC9 A0A6A5Q449 A0A6L0YA22
• Total number of polymer chains: 34
• Total formula weight: 707744.57

Authors

Groll, M.,Hines, J.,Fahnestock, M.,Crews, M.C. (deposition date: 2008-05-07, release date: 2008-06-10, Last modification date: 2024-10-16)

Primary citation

Hines, J.,Groll, M.,Fahnestock, M.,Crews, C.M.
Proteasome Inhibition by Fellutamide B Induces Nerve Growth Factor Synthesis
Chem.Biol., 15:501-512, 2008

PubMed Abstract: 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.

PubMed: 18482702
DOI: 10.1016/j.chembiol.2008.03.020

Experimental method

X-RAY DIFFRACTION (2.6 Å)