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Conformational Flexibility in the Binding Surface of the Potassium Channel Blocker ShK
Author(s) -
Sher Inbal,
Chang Shih Chieh,
Li Ying,
Chhabra Sandeep,
Palmer Arthur G.,
Norton Raymond S.,
Chill Jordan H.
Publication year - 2014
Publication title -
chembiochem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.05
H-Index - 126
eISSN - 1439-7633
pISSN - 1439-4227
DOI - 10.1002/cbic.201402295
Subject(s) - conformational isomerism , chemistry , potassium channel blocker , potassium channel , amide , helix (gastropod) , stereochemistry , binding site , relaxation (psychology) , biophysics , crystallography , potassium , molecule , biochemistry , organic chemistry , psychology , ecology , social psychology , snail , biology
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 15 N 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 15 N 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.