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Structural modeling of membrane transporter proteins
Stockholm University, Faculty of Science, Department of Physical, Inorganic and Structural Chemistry.
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.
Keyword [en]
membrane protein structure, membrane protein crystallography, membrane protein structure modelling
National Category
Other Industrial Biotechnology
Research subject
Structural Chemistry
Identifiers
URN: urn:nbn:se:su:diva-7402ISBN: 978-91-7155-590-8 (print)OAI: oai:DiVA.org:su-7402DiVA: diva2:198200
Public defence
2008-03-19, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 12 A, Stockholm, 10:00
Opponent
Supervisors
Available from: 2008-02-27 Created: 2008-02-27Bibliographically approved
List of papers
1. Homology Modeling of the Human Microsomal Glucose 6-Phosphate Transporter Explains the Mutations That Cause the Glycogen Storage Disease Type Ib
Open this publication in new window or tab >>Homology Modeling of the Human Microsomal Glucose 6-Phosphate Transporter Explains the Mutations That Cause the Glycogen Storage Disease Type Ib
2004 (English)In: Biochemistry, ISSN 0006-2960, E-ISSN 1520-4995, Vol. 43, 9289-9297 p.Article in journal (Refereed) Published
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-24724 (URN)
Available from: 2008-02-27 Created: 2008-02-27 Last updated: 2013-12-03Bibliographically approved
2. Computational modeling explains substrate binding in microsomal glucose-6-phosphate transport
Open this publication in new window or tab >>Computational modeling explains substrate binding in microsomal glucose-6-phosphate transport
Manuscript (Other academic)
Identifiers
urn:nbn:se:su:diva-24725 (URN)
Note
Part of urn:nbn:se:su:diva-7402Available from: 2008-02-27 Created: 2008-02-27 Last updated: 2010-01-13Bibliographically approved
3. Docking and homology modeling explain inhibition of the human vesicular glutamate transporters
Open this publication in new window or tab >>Docking and homology modeling explain inhibition of the human vesicular glutamate transporters
Show others...
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.

Keyword
vesicular glutamate transporter; homology modeling; membrane protein structure; inhibitor; docking; molecular dynamics
National Category
Natural Sciences
Identifiers
urn:nbn:se:su:diva-24726 (URN)000249237100002 ()
Available from: 2008-02-27 Created: 2008-02-27 Last updated: 2011-09-09Bibliographically approved
4. Salt-bridge dynamics control substrate-induced conformational change in the membrane transporter GlpT
Open this publication in new window or tab >>Salt-bridge dynamics control substrate-induced conformational change in the membrane transporter GlpT
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2008 (English)In: Journal of Molecular Biology, ISSN 0022-2836, E-ISSN 1089-8638, Vol. 378, no 4, 828-839 p.Article in journal (Refereed) Published
Abstract [en]

Active transport of substrates across cytoplasmic membranes is of great physiological, medical and pharmaceutical importance. The glycerol-3-phosphate (G3P) transporter (GlpT) of the E. coli inner membrane is a secondary active antiporter from the ubiquitous major facilitator superfamily that couples the import of G3P to the efflux of inorganic phosphate (Pi) down its concentration gradient. Integrating information from a novel combination of structural, molecular dynamics simulations and biochemical studies, we identify the residues involved directly in binding of substrate to the inward-facing conformation of GlpT, thus defining the structural basis for the substrate-specificity of this transporter. The substrate binding mechanism involves protonation of a histidine residue at the binding site. Furthermore, our data suggest that the formation and breaking of inter- and intradomain salt bridges control the conformational change of the transporter that accompanies substrate translocation across the membrane. The mechanism we propose may be a paradigm for organophosphate:phosphate antiporters.

Keyword
antiporter; membrane transport; major facilitator superfamily; molecular dynamics simulations; secondary active transport
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:su:diva-24727 (URN)10.1016/j.jmb.2008.03.029 (DOI)000256180100006 ()
Available from: 2008-02-27 Created: 2008-02-27 Last updated: 2012-06-26Bibliographically approved

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