Targeting Infectious Disease: Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosis

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Jansson, Anna M.,1979-Uppsala universitet,Struktur- och molekylärbiologi,T. Alwyn Jones (author)

Targeting Infectious Disease : Structural and functional studies of proteins from two RNA viruses and Mycobacterium tuberculosis

BookEnglish2013

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Uppsala :Acta Universitatis Upsaliensis,2013
59 s.
electronicrdacarrier

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LIBRIS-ID:oai:DiVA.org:uu-196623
ISBN:9789155486181
https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-196623URI

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Language:English
Summary in:English

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Subject category:dok swepub-publicationtype

Notes

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.

Subject headings and genre

NATURVETENSKAP Biologi Strukturbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Structural Biology hsv//eng
NATURVETENSKAP Biologi Biokemi och molekylärbiologi hsv//swe
NATURAL SCIENCES Biological Sciences Biochemistry and Molecular Biology hsv//eng
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
Biology with specialization in Structural Biology
Biologi med inriktning mot strukturbiologi
Biology with specialization in Molecular Biology
Biologi med inriktning mot molekylärbiologi
Biokemi
Biochemistry
Medicinal Chemistry
Läkemedelskemi

Added entries (persons, corporate bodies, meetings, titles ...)

Jones, T. Alwyn,ProfessorUppsala universitet,Institutionen för cell- och molekylärbiologi (thesis advisor)
Mowbray, Sherry L.,ProfessorUppsala universitet,Institutionen för cell- och molekylärbiologi (thesis advisor)
Jones, E. Yvonne,ProfessorUniversity of Oxford, Division of Structural Biology (opponent)
Uppsala universitetStruktur- och molekylärbiologi (creator_code:org_t)

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