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Docking and homology modeling explain inhibition of the human vesicular glutamate transporters
Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
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2007 (English)In: Protein Science, ISSN 0961-8368, Vol. 16, no 9, 1819-1829 p.Article in journal (Refereed) Published
Abstract [en]

As membrane transporter proteins, VGLUT1-3 mediate the uptake of glutamate into synaptic vesicles at presynaptic nerve terminals of excitatory neural cells. This function is crucial for exocytosis and the role of glutamate as the major excitatory neurotransmitter in the central nervous system. The three transporters, sharing 76% amino acid sequence identity in humans, are highly homologous but differ in regional expression in the brain. Although little is known regarding their three- dimensional structures, hydropathy analysis on these proteins predicts 12 transmembrane segments connected by loops, a topology similar to other members in the major facilitator superfamily, where VGLUT1-3 have been phylogenetically classified. In this work, we present a three- dimensional model for the human VGLUT1 protein based on its distant bacterial homolog in the same superfamily, the glycerol- 3-phosphate transporter from Escherichia coli. This structural model, stable during molecular dynamics simulations in phospholipid bilayers solvated by water, reveals amino acid residues that face its pore and are likely to affect substrate translocation. Docking of VGLUT1 substrates to this pore localizes two different binding sites, to which inhibitors also bind with an overall trend in binding affinity that is in agreement with previously published experimental data.

Place, publisher, year, edition, pages
2007. Vol. 16, no 9, 1819-1829 p.
Keyword [en]
vesicular glutamate transporter; homology modeling; membrane protein structure; inhibitor; docking; molecular dynamics
National Category
Natural Sciences
URN: urn:nbn:se:su:diva-24726ISI: 000249237100002OAI: diva2:198198
Available from: 2008-02-27 Created: 2008-02-27 Last updated: 2011-09-09Bibliographically approved
In thesis
1. Structural modeling of membrane transporter proteins
Open this publication in new window or tab >>Structural modeling of membrane transporter proteins
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

A fundamental process of all living organisms - the transport of molecules across cellular membranes through membrane transport proteins - is investigated.

After a brief review of general properties of biological membranes follows a recollection of the major methods of membrane transport that Nature utilizes (Chapter 1). This is followed by a description of important experimental (Chapter 2) and theoretical methods (Chapter 3) for structural studies of membrane proteins. The findings on membrane protein transport in papers I-IV are then summarized (Chapter 4) and important findings are discussed. The remaining text is a discussion on relevant theoretical and experimental methods.

Place, publisher, year, edition, pages
Stockholm: Institutionen för fysikalisk kemi, oorganisk kemi och strukturkemi, 2008. 148 p.
membrane protein structure, membrane protein crystallography, membrane protein structure modelling
National Category
Other Industrial Biotechnology
Research subject
Structural Chemistry
urn:nbn:se:su:diva-7402 (URN)978-91-7155-590-8 (ISBN)
Public defence
2008-03-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Available from: 2008-02-27 Created: 2008-02-27Bibliographically approved

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Hovmöller, Sven
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