Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3.

Clues to design analogs with enhanced selectivity

N. Alessandri-Haber, A. Lecoq, S. Gasparini, G. Grangier-Macmath, G. Jacquet, Alan L. Harvey, C. de Medeiros, Edward G. Rowan, M. Gola, A. Ménez, M. Crest

Research output: Contribution to journalArticle

56 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)35653-35661
Number of pages9
JournalJournal of Biological Chemistry
Volume274
Issue number50
DOIs
Publication statusPublished - 10 Dec 1999

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Kv1.1 Potassium Channel
Kv1.3 Potassium Channel
Kv1.2 Potassium Channel
Anatomy
Binding Sites
Sea Anemones
Peptides
Alanine
Protein Isoforms

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

Cite this

Alessandri-Haber, N. ; Lecoq, A. ; Gasparini, S. ; Grangier-Macmath, G. ; Jacquet, G. ; Harvey, Alan L. ; de Medeiros, C. ; Rowan, Edward G. ; Gola, M. ; Ménez, A. ; Crest, M. / Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity. In: Journal of Biological Chemistry. 1999 ; Vol. 274, No. 50. pp. 35653-35661.
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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.",
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author = "N. Alessandri-Haber and A. Lecoq and S. Gasparini and G. Grangier-Macmath and G. Jacquet and Harvey, {Alan L.} and {de Medeiros}, C. and Rowan, {Edward G.} and M. Gola and A. M{\'e}nez and M. Crest",
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Alessandri-Haber, N, Lecoq, A, Gasparini, S, Grangier-Macmath, G, Jacquet, G, Harvey, AL, de Medeiros, C, Rowan, EG, Gola, M, Ménez, A & 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, vol. 274, no. 50, pp. 35653-35661. https://doi.org/10.1074/jbc.274.50.35653

Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3. Clues to design analogs with enhanced selectivity. / Alessandri-Haber, N.; Lecoq, A.; Gasparini, S.; Grangier-Macmath, G.; Jacquet, G.; Harvey, Alan L.; de Medeiros, C.; Rowan, Edward G.; Gola, M.; Ménez, A.; Crest, M.

In: Journal of Biological Chemistry, Vol. 274, No. 50, 10.12.1999, p. 35653-35661.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Mapping the functional anatomy of BgK on Kv1.1, Kv1.2, and Kv1.3.

T2 - Clues to design analogs with enhanced selectivity

AU - Alessandri-Haber, N.

AU - Lecoq, A.

AU - Gasparini, S.

AU - Grangier-Macmath, G.

AU - Jacquet, G.

AU - Harvey, Alan L.

AU - de Medeiros, C.

AU - Rowan, Edward G.

AU - Gola, M.

AU - Ménez, A.

AU - Crest, M.

PY - 1999/12/10

Y1 - 1999/12/10

N2 - 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.

AB - 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.

KW - amino acid substitution

KW - animals

KW - binding sites

KW - cell line

KW - cnidarian venoms

KW - female

KW - humans

KW - kidney

KW - Kv1.1 Potassium Channel

KW - Kv1.2 Potassium Channel

KW - Kv1.3 Potassium Channel

KW - lysine

KW - molecular models

KW - oocytes

KW - potassium channels

KW - voltage-gated

KW - protein conformation

KW - recombinant proteins

KW - sea anemones

KW - serine

KW - transfection

KW - tyrosine

KW - xenopus laevis

U2 - 10.1074/jbc.274.50.35653

DO - 10.1074/jbc.274.50.35653

M3 - Article

VL - 274

SP - 35653

EP - 35661

JO - Journal of Biological Chemistry

JF - Journal of Biological Chemistry

SN - 0021-9258

IS - 50

ER -