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

Journal Article · Sun Jan 01 04:00:00 EST 2006 · Molecular Microbiology

DOI:https://doi.org/10.1111/j.1365-2958.2005.05036.x· OSTI ID:914271

Hu, G; Lin, G; Wang, M; Dick, L; Xu, R; Nathan, C; Li, H

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 Angstroms resolution reveals a substrate-binding pocket with composite features of the distinct {beta}1, {beta}2 and {beta}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 a-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 octapeptides of the a-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-{beta}-(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.

• Research Organization: Brookhaven National Laboratory (BNL) National Synchrotron Light Source
• Sponsoring Organization: Doe - Office Of Science
• DOE Contract Number: AC02-98CH10886
• OSTI ID: 914271
• Report Number(s): BNL--78839-2007-JA
• Journal Information: Molecular Microbiology, Journal Name: Molecular Microbiology Journal Issue: 5 Vol. 59
• Country of Publication: United States
• Language: English

Related Subjects

36 MATERIALS SCIENCE
BORONIC ACIDS
CHEMOTHERAPY
CRYSTAL STRUCTURE
ELECTRON MICROSCOPY
MACROPHAGES
MICROSCOPY
MYCOBACTERIUM TUBERCULOSIS
RESIDUES
RESOLUTION
SPECIFICITY
SUBSTRATES
TUBERCULOSIS
national synchrotron light source