Docking of transmembrane helices into four helix bundles in the high affitiy IgE receptor

Zloh, M., Esposito, D. and Gibbons, W.A. (2001) Docking of transmembrane helices into four helix bundles in the high affitiy IgE receptor. Internet Journal of Chemistry, 4 (8).

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Abstract

Docking of Transmembrane Helices into Four Helix Bundles in the High Affinity IgE Receptor Mire Zloh,a Diego Esposito,b and William A. Gibbonsa aUniversity of London, School of Pharmacy, 29/39 Brunswick Square, London WC1N 1AX, UK bDepartment of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, United Kingdom Keywords: transmembrane helices, IgE receptor, docking Publication date: August 14, 2001 15:00:00 GMT Abstract: The high affinity IgE receptor (Fc-epsilon-RI) consists of one alpha, one beta and two identical gamma subunits and it contains 7 transmembrane (TM) helices. Since a direct experimental structure determination of this intact receptor would be complex, a combination of computational chemistry with experimental work can be used to elucidate the 3D structure. The basic structural building block in plasma membrane proteins of both prokaryotic and eukaryotic cells is the apolar, often slightly amphipathic, transmembrane alpha helix. A major problem in membrane protein structure is that the seven transmembrane helices can adopt many different spatial arrangements. Helix-helix packing plays an important role in the formation of TM helix bundles, as well as in the folding of the whole receptor. The most suitable helix-helix packing arrangements were usually found using rules derived from soluble helical proteins and by rotating the helices such that the most hydrophobic sides would face the lipids. [1] Molecular modelling and mutagenesis results [2, 3, 4] have suggested that the amino acid sequence of TM helices contains information which directs specific helix-helix interactions. In this work, spatial arrangement of the transmembrane bundle were studied, as well as , helix - helix interactions in the high affinity IgE receptor, using a nonsubjective procedure, namely a low resolution docking procedure. This procedure created 35 possible four helix bundles, that were divided into three categories: "clockwise", "anticlockwise" and "crossed-loop" arrangements. "Crossed-loop" bundles were discarded due to distance constraints imposed by connecting l oops. Those arrangements are also statistically less favourable. [5] Two four-helix bundles were chosen based upon the following criteria: agr eement with proposed topology, correct TM helix arrangement, high interaction energy between TM helices, and appropriate orientation of the hydrophobic moments towards lipid bilayer. Our results are in good agreement with lipid binding sites which were predicted using molecular mechanics. [6, 7] As in any purely modelling study, the result is not a replacement for an experimental high resolution three-dimensional structure; however, the insights obtained suggest a number of avenues for further study and form a framework for rational strategies for site-directed mutagenesis, drug binding and second messenger events.

Item Type:Article
Departments, units and centres:Department of Pharmaceutical and Biological Chemistry > Department of Pharmaceutical and Biological Chemistry
ID Code:119
Journal or Publication Title:Internet Journal of Chemistry
Deposited By:Library Staff
Deposited On:30 Aug 2007
Last Modified:02 Nov 2007 14:54

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