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Insights into the inter-ring plasticity of caseinolytic proteases from the X-ray structure of Mycobacterium tuberculosis ClpP1
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, Structural Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2007 (English)In: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 63, no 2, 249-259 p.Article in journal (Refereed) Published
Abstract [en]

Mycobacterium tuberculosis caseinolytic protease ClpP1 (Mt ClpP1) is a self-compartmentalized protease consisting of two heptameric rings stacked on top of each other, thus enclosing a catalytic chamber. Within the chamber, which can be reached through two axial pores, each of the 14 identical monomers possesses a serine protease active site. The unfolding and translocation of substrates into the chamber are mediated by associated hexameric ATPases covering the axial pores. Three crystal structures of Mt ClpP1, determined by molecular replacement, are presented in this study. Two of the models were refined to a resolution of 2.6 A and the third to 3.0 A. It was found that disorder in the handle domain affects the formation and configuration of the tetradecamer and results in condensed structures with larger equatorial pores when compared with ClpPs from other species. Additionally, this disorder accompanies conformational changes of the residues in the catalytic triad. The models also reveal structural differences within the N-terminal hairpin-loop domain, which possibly reflect the significant differences in amino-acid sequence between Mt ClpP1 and other ClpP homologues in this region.

Place, publisher, year, edition, pages
2007. Vol. 63, no 2, 249-259 p.
Keyword [en]
Caseinolytic protease, ClpP1, Mycobacterium tuberculosis, Rv2461c, Tetradecamer
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-23520DOI: 10.1107/S0907444906050530ISI: 000243495700014PubMedID: 17242518OAI: oai:DiVA.org:uu-23520DiVA: diva2:51294
Available from: 2007-01-30 Created: 2007-01-30 Last updated: 2017-12-07Bibliographically approved
In thesis
1. Structural studies of Caseinolytic protease 1 from Mycobacterium tuberculosis and Methionyl-tRNA synthetase from Mycobacterium smegmatis
Open this publication in new window or tab >>Structural studies of Caseinolytic protease 1 from Mycobacterium tuberculosis and Methionyl-tRNA synthetase from Mycobacterium smegmatis
2010 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[en]
Abstract [en]

Tuberculosis is a severe disease that causes about 2 million deaths every year. It is a worldwide threat and it is estimated that one-third of the world’s population carries the infection. The severe side effects of the present drugs, and the more than 6 months long treatment, in addition to the development of resistant bacterial strains, are the incentives for the intensified search for new drugs. In this work two potential mycobacterial drug targets have been studied: Caseinolytic protease 1 (ClpP1) from Mycobacterium tuberculosis (Mt) and Methionyl-tRNA synthetase (MetRS) from Mycobacterium smegmatis (Ms).

The X-ray stucture of ClpP1 was determined to 3.0 Å resolution. The study gives details on the tetradecameric arrangement of the enzyme. Two hepameric discs assemble to form a chamber containing the catalytic activity mediated by each of the monomers. The chamber can be reached by two pores. Comparison with the human homologue reveals important structural differences.

The X-ray studies on Ms MetRS were done to 2.3 Å and 2.8 Å resolution. The study gives details on the flexibility of the enzyme and how this is related to activity. Important findings are identification of an intermediate structure in which the methionine to be adenylated is bound in the catalytic site in a tight complex. The catalytic site and the anticodon recognizing domains are separated and the structural results indicate communication between the domains. The possibility to allosterically inhibit the enzyme is discussed.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2010. 68 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 728
Keyword
Mycobacterium tuberculosis, caseinolytic protease 1, ClpP1, Mycobacterium smegmatis, methionyl-tRNA synthetase, MetRS, X-ray crystallography
National Category
Biochemistry and Molecular Biology
Research subject
Molecular Biology
Identifiers
urn:nbn:se:uu:diva-121779 (URN)978-91-554-7769-1 (ISBN)
Public defence
2010-05-07, B41, BMC, Husargatan 3, Uppsala, 13:00 (English)
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Available from: 2010-04-16 Created: 2010-03-30 Last updated: 2012-09-18

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