title: Crystal structure of the 20 S proteasome:TMC-95A complex: a non-covalent proteasome inhibitor.
abstract: The 20 S proteasome core particle (CP), a multicatalytic protease, is involved in a variety of biologically important processes, including immune response, cell-cycle control, metabolic adaptation, stress response and cell differentiation. Therefore, selective inhibition of the CP will be one possible way to influence these essential pathways. Recently, a new class of specific proteasome inhibitors, TMC-95s, was investigated and we now present a biochemical and crystallographic characterisation of the yeast proteasome core particle in complex with the natural product TMC-95A. This unusual heterocyclic compound specifically blocks the active sites of CPs non-covalently, without modifying the nucleophilic Thr1 residue. The inhibitor is bound to the CP by specific hydrogen bonds with the main-chain atoms of the protein. Analysis of the crystal structure of the complex has revealed which portions of TMC-95s are essential for binding to the proteasome. This will form the basis for the development of synthetic selective proteasome inhibitors as promising candidates for anti-tumoral or anti-inflammatory drugs.
authors.affiliation: Max-Planck-Institut für Biochemie, Martinsried, D-82152, Germany. groll@biochem.mpg.de
authors.forename: M
authors.initials: M
authors.lastname: Groll
authors.forename: Y
authors.initials: Y
authors.lastname: Koguchi
authors.forename: R
authors.initials: R
authors.lastname: Huber
authors.forename: J
authors.initials: J
authors.lastname: Kohno
mesh_terms: D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism; D001665:Binding Sites; D018360:Crystallography, X-Ray; D003546:Cysteine Endopeptidases / Q000737:chemistry* / Q000378:metabolism*; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism*; D015195:Drug Design; D006860:Hydrogen Bonding; D008958:Models, Molecular; D009097:Multienzyme Complexes / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism; D010456:Peptides, Cyclic / Q000737:chemistry* / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D055672:Static Electricity
chemical_list: D000903:Antibiotics, Antineoplastic; D015853:Cysteine Proteinase Inhibitors; D009097:Multienzyme Complexes; D009842:Oligopeptides; D010456:Peptides, Cyclic; C408291:TMC-95A; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; C078846:epoxomicin