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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 possib...

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Bibliographic Details
Published in:Journal of molecular biology 2001-08, Vol.311 (3), p.543-548
Main Authors: Groll, M, Koguchi, Y, Huber, R, Kohno, J
Format: Article
Language:English
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Summary: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.
ISSN:0022-2836
DOI:10.1006/jmbi.2001.4869