Min Woo Sung / Camden M Driggers / Barmak Mostofian / John D Russo / Bruce L Patton / Daniel M Zuckerman / Show-Ling Shyng /
PubMed Abstract
Regulation of pancreatic K channels involves orchestrated interactions of their subunits, Kir6.2 and SUR1, and ligands. Previously we reported K channel cryo-EM structures in the presence and absence ...Regulation of pancreatic K channels involves orchestrated interactions of their subunits, Kir6.2 and SUR1, and ligands. Previously we reported K 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 K 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 PIP 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 PIP binding. Molecular dynamics simulations revealed two Kir6.2 residues, K39 and R54, that mediate both ATP and PIP binding, suggesting a mechanism for competitive gating by ATP and PIP.
EMDB-26193, PDB-7tys: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and repaglinide with Kir6.2-CTD in the up conformation Method: EM (single particle) / Resolution: 3.41 Å
EMDB-26194, PDB-7tyt: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and repaglinide with Kir6.2-CTD in the down conformation Method: EM (single particle) / Resolution: 3.6 Å
EMDB-26299, PDB-7u1e: CryoEM structure of the pancreatic ATP-sensitive potassium channel bound to ATP with Kir6.2-CTD in the down conformation Method: EM (single particle) / Resolution: 4.52 Å
EMDB-26303, PDB-7u1q: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and repaglinide with SUR1-in conformation Method: EM (single particle) / Resolution: 3.9 Å
EMDB-26304, PDB-7u1s: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and repaglinide with SUR1-out conformation Method: EM (single particle) / Resolution: 3.8 Å
EMDB-26307, PDB-7u24: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and glibenclamide with Kir6.2-CTD in the up conformation Method: EM (single particle) / Resolution: 3.58 Å
EMDB-26308: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and glibenclamide with Kir6.2-CTD in the down conformation PDB-7u6y: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel in the presence of glibenclamide and ATP with Kir6.2-CTD in the down conformation Method: EM (single particle) / Resolution: 6.8 Å
EMDB-26309: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and in the presence of carbamazepine with Kir6.2-CTD in the up conformation PDB-7u7m: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel in the presence of carbamazepine and ATP with Kir6.2-CTD in the up conformation Method: EM (single particle) / Resolution: 5.2 Å
EMDB-26312: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP with Kir6.2-CTD in the up conformation PDB-7uaa: CryoEM structure of the pancreatic ATP-sensitive potassium channel in the ATP-bound state with Kir6.2-CTD in the up conformation Method: EM (single particle) / Resolution: 5.7 Å
EMDB-26320, PDB-7uqr: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel in the apo form with Kir6.2-CTD in the down conformation Method: EM (single particle)
EMDB-26321, PDB-7u2x: Cryo-EM structure of the pancreatic ATP-sensitive potassium channel in the presence of carbamazepine and ATP with Kir6.2-CTD in the down conformation Method: EM (single particle) / Resolution: 4.1 Å
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