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Flexibility and communication within the structure of the Mycobacterium smegmatis methionyl-tRNA synthetase
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, Structural Molecular Biology.
2010 (English)In: The FEBS Journal, ISSN 1742-464X, E-ISSN 1742-4658, Vol. 277, no 19, 3947-3962 p.Article in journal (Refereed) Published
Abstract [en]

Two structures of monomeric methionyl-tRNA synthetase, from Mycobacterium smegmatis, in complex with the ligands methionine/adenosine and methionine, were analyzed by X-ray crystallography at 2.3 Å and at 2.8 Å, respectively. The structures demonstrated the flexibility of the multidomain enzyme. A new conformation of the structure was identified in which the connective peptide domain bound more closely to the catalytic domain than described previously. The KMSKS(301-305) loop in our structures was in an open and inactive conformation that differed from previous structures by a rotation of the loop of about 90° around hinges located at Asn297 and Val310. The binding of adenosine to the methionyl-tRNA synthetase methionine complex caused a shift in the KMSKS domain that brought it closer to the catalytic domain. The potential use of the adenosine-binding site for inhibitor binding was evaluated and a potential binding site for a specific allosteric inhibitor was identified.

Place, publisher, year, edition, pages
2010. Vol. 277, no 19, 3947-3962 p.
Keyword [en]
Mycobacterium smegmatis, methinoly-tRNA synthetase, methionine, adenosine
National Category
Biochemistry and Molecular Biology
Research subject
Biology with specialization in Structural Biology
Identifiers
URN: urn:nbn:se:uu:diva-121752DOI: 10.1111/j.1742-4658.2010.07784.xISI: 000281850200008OAI: oai:DiVA.org:uu-121752DiVA: diva2:306462
Available from: 2010-03-29 Created: 2010-03-29 Last updated: 2012-09-18Bibliographically 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)
Opponent
Supervisors
Available from: 2010-04-16 Created: 2010-03-30 Last updated: 2012-09-18

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Ingvarsson, Henrik

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