Conformational flexibility in the binding surface of the potassium channel blocker ShK

Inbal Sher, Shihchieh Jeff Chang, Ying Li, Sandeep Chhabra, Arthur G Palmer III, Raymond Stanley Norton, Jordan Chill

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

Abstract

ShK is a 35-residue peptide that binds with high affinity to human voltage-gated potassium channels through a conserved K-Y dyad. Here we have employed NMR measurements of backbone-amide 15N spin-relaxation rates to investigate motions of the ShK backbone. Although ShK is rigid on the ps to ns timescale, increased linewidths observed for 11 backbone-amide 15N resonances identify chemical or conformational exchange contributions to the spin relaxation. Relaxation dispersion profiles indicate that exchange between major and minor conformers occurs on the sub-millisecond timescale. Affected residues are mostly clustered around the central helix-kink-helix structure and the critical K22-Y23 motif. We suggest that the less structured minor conformer increases the exposure of Y23, known to contribute to binding affinity and selectivity, thereby facilitating its interaction with potassium channels. These findings have potential implications for the design of new channel blockers based on ShK.
Original languageEnglish
Pages (from-to)2402 - 2410
Number of pages9
JournalChemBioChem
Volume15
Issue number16
DOIs
Publication statusPublished - 2014

Cite this

Sher, I., Chang, S. J., Li, Y., Chhabra, S., Palmer III, A. G., Norton, R. S., & Chill, J. (2014). Conformational flexibility in the binding surface of the potassium channel blocker ShK. ChemBioChem, 15(16), 2402 - 2410. https://doi.org/10.1002/cbic.201402295
Sher, Inbal ; Chang, Shihchieh Jeff ; Li, Ying ; Chhabra, Sandeep ; Palmer III, Arthur G ; Norton, Raymond Stanley ; Chill, Jordan. / Conformational flexibility in the binding surface of the potassium channel blocker ShK. In: ChemBioChem. 2014 ; Vol. 15, No. 16. pp. 2402 - 2410.
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abstract = "ShK is a 35-residue peptide that binds with high affinity to human voltage-gated potassium channels through a conserved K-Y dyad. Here we have employed NMR measurements of backbone-amide 15N spin-relaxation rates to investigate motions of the ShK backbone. Although ShK is rigid on the ps to ns timescale, increased linewidths observed for 11 backbone-amide 15N resonances identify chemical or conformational exchange contributions to the spin relaxation. Relaxation dispersion profiles indicate that exchange between major and minor conformers occurs on the sub-millisecond timescale. Affected residues are mostly clustered around the central helix-kink-helix structure and the critical K22-Y23 motif. We suggest that the less structured minor conformer increases the exposure of Y23, known to contribute to binding affinity and selectivity, thereby facilitating its interaction with potassium channels. These findings have potential implications for the design of new channel blockers based on ShK.",
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Sher, I, Chang, SJ, Li, Y, Chhabra, S, Palmer III, AG, Norton, RS & Chill, J 2014, 'Conformational flexibility in the binding surface of the potassium channel blocker ShK', ChemBioChem, vol. 15, no. 16, pp. 2402 - 2410. https://doi.org/10.1002/cbic.201402295

Conformational flexibility in the binding surface of the potassium channel blocker ShK. / Sher, Inbal; Chang, Shihchieh Jeff; Li, Ying; Chhabra, Sandeep; Palmer III, Arthur G; Norton, Raymond Stanley; Chill, Jordan.

In: ChemBioChem, Vol. 15, No. 16, 2014, p. 2402 - 2410.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Sher, Inbal

AU - Chang, Shihchieh Jeff

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AU - Norton, Raymond Stanley

AU - Chill, Jordan

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