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Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. : Clues to design analogs with enhanced selectivity

Alessandri-Haber, N. and Lecoq, A. and Gasparini, S. and Grangier-Macmath, G. and Jacquet, G. and Harvey, Alan L. and de Medeiros, C. and Rowan, Edward G. and Gola, M. and Ménez, A. and Crest, M. (1999) Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. : Clues to design analogs with enhanced selectivity. Journal of Biological Chemistry, 274 (50). pp. 35653-35661. ISSN 0021-9258

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Abstract

BgK is a peptide from the sea anemone Bunodosoma granulifera, which blocks Kv1.1, Kv1.2, and Kv1.3 potassium channels. Using 25 analogs substituted at a single position by an alanine residue, we performed the complete mapping of the BgK binding sites for the three Kv1 channels. These binding sites included three common residues (Ser-23, Lys-25, and Tyr-26) and a variable set of additional residues depending on the particular channel. Shortening the side chain of Lys-25 by taking out the four methylene groups dramatically decreased the BgK affinity to all Kv1 channels tested. However, the analog K25Orn displayed increased potency on Kv1.2, which makes this peptide a selective blocker for Kv1.2 (K(D) 50- and 300-fold lower than for Kv1.1 and Kv1.3, respectively). BgK analogs with enhanced selectivity could also be made by substituting residues that are differentially involved in the binding to some of the three Kv1 channels. For example, the analog F6A was found to be >500-fold more potent for Kv1.1 than for Kv1.2 and Kv1.3. These results provide new information about the mechanisms by which a channel blocker distinguishes individual channels among closely related isoforms and give clues for designing analogs with enhanced selectivity.

Item type: Article
ID code: 17508
Notes: Strathprints' policy is to record up to 8 authors per publication, plus any additional authors based at the University of Strathclyde. More authors may be listed on the official publication than appear in the Strathprints' record.
Keywords: amino acid substitution, animals, binding sites, cell line, cnidarian venoms, female, humans, kidney, Kv1.1 Potassium Channel, Kv1.2 Potassium Channel, Kv1.3 Potassium Channel, lysine, molecular models, oocytes, potassium channels, voltage-gated, protein conformation, recombinant proteins, sea anemones, serine, transfection, tyrosine, xenopus laevis, Pharmacy and materia medica, Biochemistry, Cell Biology, Molecular Biology
Subjects: Medicine > Pharmacy and materia medica
Department: Faculty of Science > Strathclyde Institute of Pharmacy and Biomedical Sciences
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    Depositing user: Strathprints Administrator
    Date Deposited: 22 Apr 2010 09:42
    Last modified: 05 Sep 2014 01:07
    URI: http://strathprints.strath.ac.uk/id/eprint/17508

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