7TYT

Cryo-EM structure of the pancreatic ATP-sensitive potassium channel bound to ATP and repaglinide with Kir6.2-CTD in the down conformation

Summary for 7TYT

• Entry DOI: 10.2210/pdb7tyt/pdb
• EMDB information: 20528 26194
• Descriptor: ATP-sensitive inward rectifier potassium channel 11, ATP-binding cassette sub-family C member 8, 2-acetamido-2-deoxy-beta-D-glucopyranose-(1-4)-2-acetamido-2-deoxy-beta-D-glucopyranose, ... (9 entities in total)
• Functional Keywords: katp channel, sur1, kir6.2, repaglinide, rpg, sulfonylurea receptor, potassium transport, membrane protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 5
• Total formula weight: 365221.38

Authors

Shyng, S.L.,Sung, M.W.,Driggers, C.M. (deposition date: 2022-02-14, release date: 2022-08-31, Last modification date: 2024-11-13)

Primary citation

Sung, M.W.,Driggers, C.M.,Mostofian, B.,Russo, J.D.,Patton, B.L.,Zuckerman, D.M.,Shyng, S.L.
Ligand-mediated Structural Dynamics of a Mammalian Pancreatic K ATP Channel.
J.Mol.Biol., 434:167789-167789, 2022

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 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.

PubMed: 35964676
DOI: 10.1016/j.jmb.2022.167789

Experimental method

ELECTRON MICROSCOPY (3.6 Å)