uu.seUppsala University Publications
Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Structure of Mycobacterium tuberculosis glutamine synthetase in complex with a transition-state mimic provides functional insights
Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology.
2005 In: Proc. Natl. Acad. Sci. USA, ISSN 0027-8424, Vol. 102, no 30, 10499-10504 p.Article in journal (Refereed) Published
Place, publisher, year, edition, pages
2005. Vol. 102, no 30, 10499-10504 p.
Identifiers
URN: urn:nbn:se:uu:diva-97543OAI: oai:DiVA.org:uu-97543DiVA: diva2:172532
Available from: 2008-09-25 Created: 2008-09-25 Last updated: 2016-05-09Bibliographically approved
In thesis
1. Structural Studies of Glutamine Synthetases – Towards the Development of Novel Antitubercular Agents
Open this publication in new window or tab >>Structural Studies of Glutamine Synthetases – Towards the Development of Novel Antitubercular Agents
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Glutamine synthetase (GS) plays an important role in nitrogen metabolism, where it catalyzes the ATP-dependent condensation of glutamate and ammonia to yield glutamine. Recent studies showed the importance of M. tuberculosis GS (MtGS) for growth and survival of the bacterium, and demonstrated its potential as a drug target.

This thesis presents structural studies of MtGS and mammalian GSs, which are aimed at identifying and developing novel inhibitors against the mycobacterial target.

The structure of MtGS was solved in complex with a phosphorylated form of the inhibitor methionine sulfoximine, magnesium and ADP. The complex structure provides a detailed picture of the active site, offering several insights into catalysis and inhibition, as well as forming a solid basis for structure-based drug design.

The apo canine GS and liganded human GS structures described in this thesis represent the first structures of the mammalian enzymes. Comparison of the structures revealed substrate-induced conformational changes. Inspection of the nucleotide-binding site showed that it differs from that of MtGS, thus offering good opportunities to design specific and selective inhibitors of the mycobacterial enzyme.

The amino acid-binding site of MtGS was evaluated as a target for inhibition, using a combination of a literature survey, structure-based virtual screening and the synthesis of a small library of compounds. As a result, several new inhibitors of MtGS could be identified.

Finally, the structural basis for inhibition of MtGS by a purine analogue (PA) is provided. PA, an analogue of a class of compounds found to inhibit MtGS in a high-throughput screening assay, targets the nucleotide-binding site. The architecture of the HsGS nucleotide-binding site indicates that PA would not be able to bind to the human enzyme, offering good prospects for selective inhibition of MtGS.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 48 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 553
National Category
Structural Biology
Identifiers
urn:nbn:se:uu:diva-9286 (URN)978-91-554-7283-2 (ISBN)
Public defence
2008-10-17, B21, BMC, Husargatan 3, Uppsala, 13:00 (English)
Opponent
Supervisors
Available from: 2008-09-25 Created: 2008-09-25 Last updated: 2009-06-01Bibliographically approved

Open Access in DiVA

No full text

Authority records BETA

Mowbray, Sherry L.

Search in DiVA

By author/editor
Mowbray, Sherry L.
By organisation
Department of Cell and Molecular Biology

Search outside of DiVA

GoogleGoogle Scholar

urn-nbn

Altmetric score

urn-nbn
Total: 448 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf