Characterizing the structural basis of Kv7 Ion Channel modulation

NAISS 2023/1-3


NAISS Large Compute

Principal Investigator:

Sara Liin


Linköpings universitet

Start Date:


End Date:


Primary Classification:

10603: Biophysics

Secondary Classification:

10407: Theoretical Chemistry



Ion channels facilitate the ‘electrical signals of life’ by opening, closing, and desensitizing to regulate the flow of ions across the cellular membrane. The Kv7 is one such family of ion channels that conducts Potassium ion efflux in-response to a depolarization of the transmembrane potential (Fig. 1). Five isoforms termed Kv7.1 to Kv7.5 makeup this family of channels and are ubiquitously distributed across a range of tissues. The proteins play a role in multiple physiological processes and are implicated in a range of disorders including long-QT syndrome, epilepsy, deafness, and loss of bladder control. Despite this prevalence of Kv7-associated disorders, no approved pharmaceutical intervention targeted at the channels exists. In fact, the only two approved Kv7 channel openers – Retigabine and Flupirtine were both withdrawn due to undesirable off-target effects. While a rich pharmacology of molecules are capable of modulating Kv7 function, they target a variety of binding sites and more importantly display a lack of subtype-specificity. Ongoing experimental research within the laboratory has however identified a slew of novel endogenous and exogenous molecules – endocannabinoids, polyunsaturated fatty acids, steroids, and lipids capable of modulating Kv7 ion channels in a state- and subtype-specific manner. The leveraging of these preliminary findings towards novel drug development requires a piecewise tackling of multiple questions. Firstly, what are the specific binding sites for the molecules? Secondly, what are the residues that coordinate ligand-binding? Finally, what is the structural mechanism underlying the ligand’s functional modulation? For this, the project takes advantage of recent advances in cryo-electron microscopy protocols and structure prediction techniques like Alphafold2 that have together provided an array of atomistic resolution structures of the Kv7 voltage-gated ion channels. Utilizing coarse-grain and atomistic molecular dynamics simulations of these structures, the project aims to identify modulator binding sites, the residues coordinating ligand binding and the mechanisms of drug action. The results of the project can enhance understanding of drug modulation of Kv7 function and open avenues for the development of channelopathy-specific drugs selectively targeting specific members of the Kv7 ion channel family.