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Structure and biochemical function studies of Mycobacterium tuberculosis essential protein Rv3778c
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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Manuscript (Other academic)
URN: urn:nbn:se:uu:diva-96921OAI: oai:DiVA.org:uu-96921DiVA: diva2:171657
Available from: 2008-03-20 Created: 2008-03-20 Last updated: 2016-05-12Bibliographically approved
In thesis
1. Targeting Mycobacterium tuberculosis Proteins: Structure and Function Studies of Five Essential Proteins
Open this publication in new window or tab >>Targeting Mycobacterium tuberculosis Proteins: Structure and Function Studies of Five Essential Proteins
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

This thesis describes the target selection, cloning, expression, purification, crystallization, structure and biochemical characterization of five essential Mycobacterium tuberculosis (Mtb) proteins. The search for drugs against the causal agent of tuberculosis is urgently needed and the targeting of essential genes is necessary to fulfill this goal.

The crystal structures of carbonic anhydrases (CA) Rv1284 and Rv3588c have been determined to 2.0 and 1.7 Å resolution, respectively. Rv3588c, in contrast to Rv1284, is an active β-CA that shows two different active site conformations and pH-dependent oligomerization states.

Rv1295 is an active threonine synthase with an unusually high pH optimum; the structure has been solved to 2.5 Å resolution, based on which a modification to the reaction mechanism published previously is proposed.

Mtb has a thick and impermeable cell envelope that constitutes an efficient barrier against drugs. One of the essential components of the envelope is mycolic acid (MA). The inhibition of enzymes participating in its synthesis would be lethal for Mtb. Rv0636, a formerly unknown-function protein has β-hydroxyacyl-ACP dehydrase activity which is essential for MA synthesis. Co-expression with partners notably improves its solubility.

Around 55% of Mtb proteins have unknown function. Rv3778c is one of them and its three-dimensional structure has been determined to 1.8 Å resolution. Studies aimed at the elucidation of its biochemical function are shown. A pathway not yet reported in Mtb is also suggested.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 61 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 411
Cell and molecular biology, carbonic anhydrase, threonine synthase, FAS II, Rv0636, Rv1284, Rv1295, Rv3588c, Rv3778c, X-ray crystallography, Cell- och molekylärbiologi, Mycobacterium tuberculosis
urn:nbn:se:uu:diva-8580 (URN)978-91-554-7134-7 (ISBN)
Public defence
2008-04-11, B42, BMC, Husargatan 3, Uppsala, 13:00 (English)
Available from: 2008-03-20 Created: 2008-03-20 Last updated: 2009-06-01Bibliographically approved

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Larsson, Anna M.Mowbray, Sherry
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