Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate

Hu, G., Lin, G., Wang, M., Dick, L., Xu, R. M., Nathan, C., Li, H. (2006) Structure of the Mycobacterium tuberculosis proteasome and mechanism of inhibition by a peptidyl boronate. Molecular Microbiology, 59 (5). pp. 1417-1428. ISSN 0950382X

URL: http://www.ingentaconnect.com/content/bsc/mole/200...
DOI: 10.1111/j.1365-2958.2005.05036.x

Abstract

Mycobacterium tuberculosis (Mtb) has the remarkable ability to resist killing by human macrophages. The 750 kDa proteasome, not available in most eubacteria except Actinomycetes, appears to contribute to Mtb's resistance. The crystal structure of the Mtb proteasome at 3.0 A? resolution reveals a substrate-binding pocket with composite features of the distinct ?1, ?2 and ?5 substrate binding sites of eukaryotic proteasomes, accounting for the broad specificity of the Mtb proteasome towards oligopeptides described in the companion article [Lin et al. (2006), Mol Microbiol doi:10.1111/j.1365-2958.2005.05035.x]. The substrate entrance at the end of the cylindrical proteasome appears open in the crystal structure due to partial disorder of the ?-subunit N-terminal residues. However, cryo-electron microscopy of the core particle reveals a closed end, compatible with the density observed in negative-staining electron microscopy that depended on the presence of the N-terminal octapetides of the ?-subunits in the companion article, suggesting that the Mtb proteasome has a gated structure. We determine for the first time the proteasomal inhibition mechanism of the dipeptidyl boronate N-(4-morpholine)carbonyl-?-(1-naphthyl)-l-alanine-l-leucine boronic acid (MLN-273), an analogue of the antimyeloma drug bortezomib. The structure improves prospects for designing Mtb-specific proteasomal inhibitors as a novel approach to chemotherapy of tuberculosis. © 2006 Blackwell Publishing Ltd.

Item Type: Paper
Subjects: Investigative techniques and equipment > microscopy > electron microscopy
organism description > bacteria > mycobactirium
diseases & disorders > bacterial Infections > tuberculosis
Investigative techniques and equipment > x ray crystallography
CSHL Authors:
Depositing User: CSHL Librarian
Date Deposited: 14 Dec 2011 14:55
Last Modified: 14 Dec 2011 14:55
URI: http://repository.cshl.edu/id/eprint/22822

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