title: Identification of the functional binding pocket for compounds targeting small-conductance Ca²⁺-activated potassium channels.
abstract: Small- and intermediate-conductance Ca(2+)-activated potassium channels, activated by Ca(2+)-bound calmodulin, have an important role in regulating membrane excitability. These channels are also linked to clinical abnormalities. A tremendous amount of effort has been devoted to developing small molecule compounds targeting these channels. However, these compounds often suffer from low potency and lack of selectivity, hindering their potential for clinical use. A key contributing factor is the lack of knowledge of the binding site(s) for these compounds. Here we demonstrate by X-ray crystallography that the binding pocket for the compounds of the 1-ethyl-2-benzimidazolinone (1-EBIO) class is located at the calmodulin-channel interface. We show that, based on structure data and molecular docking, mutations of the channel can effectively change the potency of these compounds. Our results provide insight into the molecular nature of the binding pocket and its contribution to the potency and selectivity of the compounds of the 1-EBIO class.
authors.affiliation: Department of Molecular Physiology and Biophysics, Thomas Jefferson University, 1020 Locust Street, Philadelphia, Pennsylvania 19107, USA.
authors.forename: Miao
authors.initials: M
authors.lastname: Zhang
authors.forename: John M
authors.initials: JM
authors.lastname: Pascal
authors.forename: Marcel
authors.initials: M
authors.lastname: Schumann
authors.forename: Roger S
authors.initials: RS
authors.lastname: Armen
authors.forename: Ji-Fang
authors.initials: JF
authors.lastname: Zhang
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism*; D001665:Binding Sites; D002118:Calcium / Q000378:metabolism; D002147:Calmodulin / Q000378:metabolism; D018360:Crystallography, X-Ray; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D051381:Rats; D016415:Sequence Alignment; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001562:Benzimidazoles; D002147:Calmodulin; D051640:Small-Conductance Calcium-Activated Potassium Channels; C102635:1-ethyl-2-benzimidazolinone; D002118:Calcium