Structural and biophysical properties of a synthetic channel-forming peptide: designing a clinically relevant anion selective pore

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Show simple item record Bukovnik, U. Gao, J. Cook, G. A. Shank, L. P. Seabra, M. B. Schultz, Bruce D. Iwamoto, T. Chen, J. Tomich, John M. 2012-06-22T13:56:26Z 2012-06-22T13:56:26Z 2012-06-22
dc.description.abstract The design, synthesis, modeling and in vitro testing of channel-forming peptides derived from the cys-loop superfamily of ligand-gated ion channels are part of an ongoing research focus. Over 300 different sequences have been prepared based on the M2 transmembrane segment of the spinal cord glycine receptor α-subunit. A number of these sequences are water-soluble monomers that readily insert into biological membranes where they undergo supramolecular assembly, yielding channels with a range of selectivities and conductances. Selection of a sequence for further modifications to yield an optimal lead compound came down to a few key biophysical properties: low solution concentrations that yield channel activity, greater ensemble conductance, and enhanced ion selectivity. The sequence NK[subscript]4-M2GlyR T19R, S22W (KKKKPARVGLGITTVLTMRTQW) addressed these criteria. The structure of this peptide has been analyzed by solution NMR as a monomer in detergent micelles, simulated as five-helix bundles in a membrane environment, modified by cysteine-scanning and studied for insertion efficiency in liposomes of selected lipid compositions. Taken together, these results define the structural and key biophysical properties of this sequence in a membrane. This model provides an initial scaffold from which rational substitutions can be proposed and tested to modulate anion selectivity. This article is part of a Special Issue entitled: Protein Folding in Membranes. en_US
dc.relation.uri en_US
dc.subject Channel-forming peptide en_US
dc.subject Self-assembly en_US
dc.subject Glycine receptor en_US
dc.subject Pore structure en_US
dc.title Structural and biophysical properties of a synthetic channel-forming peptide: designing a clinically relevant anion selective pore en_US
dc.type Article (author version) en_US 2012 en_US
dc.citation.doi doi:10.1016/j.bbamem.2011.07.037 en_US
dc.citation.epage 1048 en_US
dc.citation.issue 4 en_US
dc.citation.jtitle Biochimica et Biophysica Acta – Biomembranes en_US
dc.citation.spage 1039 en_US
dc.citation.volume 1818 en_US
dc.contributor.authoreid ubkov en_US
dc.contributor.authoreid jcgao en_US
dc.contributor.authoreid bschultz en_US
dc.contributor.authoreid iwamoto en_US
dc.contributor.authoreid jtomich en_US

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