PhD student Karol Sanches (Monash node) recently published a paper titled “Interaction of the Inhibitory Peptides ShK and HmK with the Voltage-Gated Potassium Channel KV1.3: Role of Conformational Dynamics” in J. Chem. Inf. Model.
In her paper, she describes the effects of KV1.3 on diseases like Alzheimer’s and Parkinson’s. KV1.3 is a voltage-gated potassium channel found in the membrane of the cells. The upregulation of KV1.3 in T lymphocytes is related to many autoimmune diseases and, in microglia, in the brains of patients with Alzheimer’s and Parkinson’s diseases and ischemic stroke. The blockage of KV1.3 is an attractive mechanism for treating autoimmune and neuroinflammatory diseases. Indeed, several peptides found in the venom of sea anemones have proven to be potent blockers of KV1.3, including the ShK from Stichodactyla helianthus, and HmK from Heteractis magnifica, both inhibitors of the KV1.3 channel.
Mutagenesis analysis have shown that both peptides block KV1.3 through the Lys-Tyr dyad. Although ShK and HmK share 60% sequence identity by BLAST, ShK is nearly 300-fold more potent against KV1.3 than HmK. We used a combination of docking and molecular dynamics (MD) simulations to investigate the conformational dynamics in ShK and HmK and the implications of this flexibility for channel recognition. Besides sharing high sequence and structure identity, the dynamics of ShK and HmK differ. While HmK is highly rigid, ShK is dynamic, sampling three major configurations. Both peptides bind to KV1.3 with Lys22 occupying the channel’s pore; intriguingly, the more flexible peptide, ShK, binds with significantly higher affinity than HmK.
Find the full paper here.
ARC Centre for Fragment-Based Design 