Abstract
| Original language | English |
|---|---|
| Pages (from-to) | 2402 - 2410 |
| Number of pages | 9 |
| Journal | ChemBioChem |
| Volume | 15 |
| Issue number | 16 |
| DOIs | |
| Publication status | Published - 2014 |
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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 journal › Article › Research › peer-review
TY - JOUR
T1 - Conformational flexibility in the binding surface of the potassium channel blocker ShK
AU - Sher, Inbal
AU - Chang, Shihchieh Jeff
AU - Li, Ying
AU - Chhabra, Sandeep
AU - Palmer III, Arthur G
AU - Norton, Raymond Stanley
AU - Chill, Jordan
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
UR - http://onlinelibrary.wiley.com/doi/10.1002/cbic.201402295/epdf
U2 - 10.1002/cbic.201402295
DO - 10.1002/cbic.201402295
M3 - Article
VL - 15
SP - 2402
EP - 2410
JO - ChemBioChem
JF - ChemBioChem
SN - 1439-4227
IS - 16
ER -