title: Structural investigation of proteasome inhibition.
abstract: The novel proteolytic mechanism of the 20S proteasome from T. acidophilum has been investigated by X-ray crystallography using small-molecule inhibitors and substrate analogues. The 20S proteasome degrades unfolded substrates into small peptides of a defined length. Calpain inhibitor II, chymostatin and lactacystin all bind in the previously identified active site pocket near Thr1 of all fourteen beta-subunits. The chromogenic substrate analogue Suc-LLVY-AMC binds in the same pocket of the proteolytically inactive T1A mutant of the beta-subunit, but with a significantly altered geometry. The heavy-atom cluster Ta6Br12(2+) used in X-ray structure determination occupies seven sites in the inner compartment of the proteasome and exhibits inhibition of the chymotrypsin-like activity. Other effectors of proteasome activity showed no significant difference in electron density.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, Germany.
authors.forename: L
authors.initials: L
authors.lastname: Ditzel
authors.forename: D
authors.initials: D
authors.lastname: Stock
authors.forename: J
authors.initials: J
authors.lastname: Löwe
mesh_terms: D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D001965:Bromides / Q000737:chemistry; D002154:Calpain / Q000037:antagonists & inhibitors; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D009097:Multienzyme Complexes / Q000737:chemistry* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D013635:Tantalum / Q000737:chemistry
chemical_list: D001965:Bromides; D015853:Cysteine Proteinase Inhibitors; D004791:Enzyme Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; C067713:lactacystin; C107153:tantalum bromide; D013635:Tantalum; C002101:chymostatin; D002154:Calpain; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine