Structural Determinants for Ligand Accommodation in Voltage Sensors

Abstract

After ligand binding, many ion channels undergo rearrangements at the voltage sensor domain (VSD) that often modulate their gating activity with important physiological repercussions. Since the VSD is dynamic, it is interesting to establish a correlation between the potential mobility of this element in terms of its intrinsic flexibility and its ability to accommodate several ligands by induced-fit mechanisms. We presume that these associations are not causal since the flexibility of the VSD could have an important impact on the ligand coupling event. Many significantly flexible ion channels show a general architecture and composition compatible with important conformational changes and capable of accommodating chemically diverse agonists. In this contribution, the structural bases of this subtle and probably unexpected relationship between the VSD flexibility and its influence during the dynamic coupling of the ligand are exposed. Thus, given its physiological relevance, the study of ion channel malfunction can be associated with ligand accommodation events to the VSD, which could depend on its local flexibility. This could contribute to a better understanding of the molecular bases of a variety of physiological disorders. In consequence, considering these effects during the protein/ligand interaction could be determinant to the rational design of novel drugs.