tmc-95a has been researched along with epoxomicin* in 2 studies
2 other study(ies) available for tmc-95a and epoxomicin
Article | Year |
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Probing structural determinants distal to the site of hydrolysis that control substrate specificity of the 20S proteasome.
The 20S proteasome is a large multicomponent protease complex. Relatively little is known about the mechanisms that control substrate specificity of its multiple active sites. We present here the crystal structure at 2.95 A resolution of a beta2-selective inhibitor (MB1) bound to the yeast 20S proteasome core particle (CP). This structure is compared to the structure of the CP bound to a general inhibitor (MB2) that covalently modified all three (beta1, beta2, beta5) catalytic subunits. These two inhibitors differ only in their P3 and P4 residues, thereby highlighting binding interactions distal to the active site threonine that control absolute substrate specificity of the complex. Comparisons of the CP-bound structures of MB1, MB2, and the natural products epoxomycin and TMC-95A also provide information regarding general binding modes for several classes of proteasome inhibitors. Topics: Binding Sites; Crystallography; Cysteine Endopeptidases; Enzyme Inhibitors; Models, Molecular; Multienzyme Complexes; Oligopeptides; Peptides, Cyclic; Proteasome Endopeptidase Complex; Protein Binding; Protein Structure, Tertiary; Protein Subunits; Saccharomyces cerevisiae Proteins; Structure-Activity Relationship; Substrate Specificity; Sulfones | 2002 |
Crystal structure of the 20 S proteasome:TMC-95A complex: a non-covalent proteasome inhibitor.
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. Topics: Antibiotics, Antineoplastic; Binding Sites; Crystallography, X-Ray; Cysteine Endopeptidases; Cysteine Proteinase Inhibitors; Drug Design; Hydrogen Bonding; Models, Molecular; Multienzyme Complexes; Oligopeptides; Peptides, Cyclic; Proteasome Endopeptidase Complex; Protein Conformation; Protein Structure, Secondary; Saccharomyces cerevisiae; Static Electricity | 2001 |