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Structure of the methyltransferase domain from the Modoc virus, a flavivirus with no known vector
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
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2009 (English)In: Acta Crystallographica Section D: Biological Crystallography, ISSN 0907-4449, E-ISSN 1399-0047, Vol. 65, 796-803 p.Article in journal (Refereed) Published
Abstract [en]

The Modoc virus (MODV) is a flavivirus with no known vector (NKV). Evolutionary studies have shown that the viruses in the MODV group have evolved in association with mammals (bats, rodents) without transmission by an arthropod vector. MODV methyltransferase is the first enzyme from this evolutionary branch to be structurally characterized. The high-resolution structure of the methyltransferase domain of the MODV NS5 protein (MTase(MODV)) was determined. The protein structure was solved in the apo form and in complex with its cofactor S-adenosyl-l-methionine (SAM). Although it belongs to a separate evolutionary branch, MTase(MODV) shares structural characteristics with flaviviral MTases from the other branches. Its capping machinery is a relatively new target in flaviviral drug development and the observed structural conservation between the three flaviviral branches indicates that it may be possible to identify a drug that targets a range of flaviviruses. The structural conservation also supports the choice of MODV as a possible model for flavivirus studies.

Place, publisher, year, edition, pages
2009. Vol. 65, 796-803 p.
National Category
Biological Sciences
Identifiers
URN: urn:nbn:se:uu:diva-128367DOI: 10.1107/S0907444909017260ISI: 000268136800008OAI: oai:DiVA.org:uu-128367DiVA: diva2:331410
Available from: 2010-07-22 Created: 2010-07-20 Last updated: 2017-12-12Bibliographically approved
In thesis
1. Targeting Infectious Disease: Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosis
Open this publication in new window or tab >>Targeting Infectious Disease: Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosis
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The recent emergence of a number of new viral diseases as well as the re-emergence of tuberculosis (TB), indicate an urgent need for new drugs against viral and bacterial infections.

Coronavirus nsp1 has been shown to induce suppression of host gene expression and interfere with host immune response. However, the mechanism behind this is currently unknown. Here we present the first nsp1 structure from an alphacoronavirus, Transmissible gastroenteritis virus (TGEV) nsp1. Contrary to previous speculation, the TGEV nsp1 structure clearly shows that alpha- and betacoronavirus nsp1s have a common evolutionary origin. However, differences in conservation, shape and surface electrostatics indicate that the mechanism for nsp1-induced suppression of host mRNA translation is likely to be different in the alpha- and betacoronavirus genera.

The Modoc virus is a neuroinvasive rodent virus with similar pathology as flavivirus encephalitis in humans. The flaviviral methyltransferase catalyses the two methylations required to complete 5´ mRNA capping, essential for mRNA stability and translation. The structure of the Modoc NS5 methyltransferase domain was determined in complex with its cofactor S-adenosyl-L-methionine. The observed methyltransferase conservation between Modoc and other flaviviral branches, indicates that it may be possible to identify drugs that target a range of flaviviruses and supports the use of Modoc virus as a model for general flaviviral studies.

1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is part of the methylerythritol phosphate (MEP) pathway that produces essential precursors for isoprenoid biosynthesis. This pathway is used by a number of pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, but it is not present in humans. Using a structure-based approach, we designed a number of MtDXR inhibitors, including a novel fosmidomycin-analogue that exhibited improved activity against P.falciparum in an in vitro blood cell growth assay. The approach also allowed the first design of an inhibitor that bridge both DXR substrate and co-factor binding sites, providing a stepping-stone for further optimization.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2013. 59 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 1028
Keyword
RNA virus, coronavirus, alphacoronavirus, nsp1, TGEV, flavivirus, Modoc virus, NS5, methyltransferase, mRNA capping, Mycobacterium tuberculosis, tuberculosis, 1-deoxy-D-xylulose 5-phosphate reductoisomerase, DXR, fosmidomycin analogues, MEP pathway, drug development, xray-crystallography
National Category
Structural Biology Biochemistry and Molecular Biology
Research subject
Biology with specialization in Structural Biology; Biology with specialization in Molecular Biology; Biochemistry; Medicinal Chemistry
Identifiers
urn:nbn:se:uu:diva-196623 (URN)978-91-554-8618-1 (ISBN)
Public defence
2013-04-26, B42, Biomedical Center, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Funder
Swedish Research CouncilSwedish Foundation for Strategic Research
Available from: 2013-04-05 Created: 2013-03-11 Last updated: 2013-08-30Bibliographically approved

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