7u24 | pdb_00007u24
Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and glibenclamide with Kir6.2-CTD in the up conformation
Structural highlights
Function[KCJ11_RAT] This receptor is controlled by G proteins. Inward rectifier potassium channels are characterized by a greater tendency to allow potassium to flow into the cell rather than out of it. Their voltage dependence is regulated by the concentration of extracellular potassium; as external potassium is raised, the voltage range of the channel opening shifts to more positive voltages. The inward rectification is mainly due to the blockage of outward current by internal magnesium. Can be blocked by extracellular barium. Can form cardiac and smooth muscle-type KATP channels with ABCC9. KCNJ11 forms the channel pore while ABCC9 is required for activation and regulation (By similarity). Publication Abstract from PubMedRegulation of pancreatic KATP channels involves orchestrated interactions of their subunits, Kir6.2 and SUR1, and ligands. Previously we reported KATP channel cryo-EM structures in the presence and absence of pharmacological inhibitors and ATP, focusing on the mechanisms by which inhibitors act as pharmacological chaperones of KATP channels (Martin et al., 2019). Here we analyzed the same cryo-EM datasets with a focus on channel conformational dynamics to elucidate structural correlates pertinent to ligand interactions and channel gating. We found pharmacological inhibitors and ATP enrich a channel conformation in which the Kir6.2 cytoplasmic domain is closely associated with the transmembrane domain, while depleting one where the Kir6.2 cytoplasmic domain is extended away into the cytoplasm. This conformational change remodels a network of intra- and inter-subunit interactions as well as the ATP and PIP2 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 and showed a SUR1 residue, K134, participates in PIP2 binding. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP2 binding, suggesting a mechanism for competitive gating by ATP and PIP2. Ligand-mediated Structural Dynamics of a Mammalian Pancreatic KATP Channel.,Sung MW, Driggers CM, Mostofian B, Russo JD, Patton BL, Zuckerman DM, Shyng SL J Mol Biol. 2022 Aug 11;434(19):167789. doi: 10.1016/j.jmb.2022.167789. PMID:35964676[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
| ||||||||||||||||||
