The roles of serine and threonine sidechains in ion channels: a modelling study |
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Authors: | Mark S P Sansom |
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Institution: | (1) Laboratory of Molecular Biophysics, The Rex Richards Building, University of Oxford, South Parks Road, OX1 3QU Oxford, UK |
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Abstract: | The ion channel of the nicotinic acetylcholine receptor (nAChR) is believed to be lined by transmembrane M2 helices. A 4-8-12 sequence motif, comprising serine (S) or threonine (T) residues at positions 4, 8 and 12 of M2, is conserved between different members, anion and cation selective, of the nAChR superfamily. Parallel bundles of 4-8-12 motif-containing helices are considered as simplified models of ion channels. The relationship between S and T sidechain conformations and channelion interactions is explored via evaluation of interaction energies of K+ and of Cl– ions with channel models. Energy calculations are used to determine optimal 2 (C-C\-O-H) values in the presence of K+ or Cl– ions. 4-8-12 motif-containing bundles may form favourable interactions with either cations or anions, dependent upon the 2 values adopted. Parallel-helix and tilted-helix bundles are considered, as are heteromeric models designed to mimic the Torpedo nAChR. The main conclusion of the study is that conformational flexibility at 2 enables both S and T residues to form favourable interactions with anions or cations. Consequently, there is apparently no difference between S and T residues in their interactions with permeant ions, which suggests that the presence of T vs. S residues within the 4-8-12 motif is not a major mechanism whereby anion/cation selectivity may be generated. The implications of these studies with respect to more elaborate models of nAChR and related receptors are considered.Abbreviations nAChR, GluR, NMDA-R, 5HT3-R, GABAAR, GlyR
nicotinic acetylcholine, glutamate, NMDA, 5HT3, GABAA and glycine receptors, respectively
- PhTx
philanthotoxin
- M2
second membrane-spanning helix of receptor-channel subunits |
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Keywords: | Ion channel Nicotinic receptor -helix bundle" target="_blank">gif" alt="agr" align="BASELINE" BORDER="0">-helix bundle Molecular modelling |
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