Conformational Flexibility in the Binding Surface of the Potassium Channel Blocker ShK |
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| Authors: | Inbal Sher Shih Chieh Chang Dr. Ying Li Dr. Sandeep Chhabra Prof. Arthur G. Palmer III Prof. Raymond S. Norton Dr. Jordan H. Chill |
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| Affiliation: | 1. Department of Chemistry, Bar Ilan University, Ramat Gan 52900 (Israel);2. Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, 381 Royal Parade, Parkville, Victoria 3052 (Australia);3. Department of Biochemistry and Molecular Biophysics, Columbia University, 630 West 168th Street, New York, NY 10032 (USA);4. Present address: Department of Chemistry, University of Louisville, 2320 South Brook Street, Louisville, KY 40292 (USA) |
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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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| Keywords: | NMR spectroscopy potassium channel blockers protein dynamics relaxation dispersion structural biology |
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