Ligand-mediated structural dynamics of a mammalian pancreatic KATP channel

Abstract

Abstract Regulation of pancreatic K ATP channels involves orchestrated interactions of channel subunits, Kir6.2 and SUR1, and their ligands. How ligand interactions affect channel conformations and activity is not well understood. To elucidate the structural correlates pertinent to ligand interactions and channel gating, we compared cryo-EM structures of channels in the presence and absence of pharmacological inhibitors and ATP, focusing on channel conformational dynamics. We found pharmacological inhibitors and ATP enrich a channel conformation in which the Kir6.2 cytoplasmic domain is closely associated with the transmembrane domain relative to one where the Kir6.2 cytoplasmic domain is extended away into the cytoplasm. This conformation change remodels a network of intra and inter-subunit interactions as well as both the ATP and PIP 2 binding pockets. The structures resolved key contacts between the distal N-terminus of Kir6.2 and SUR1’s ABC module involving residues implicated in channel function. A SUR1 residue, K134, is identified to directly contribute to the PIP 2 binding pocket. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP 2 binding, suggesting a mechanism for competitive gating by ATP and PIP 2 .