8TI2

Cryo-EM structure of a SUR1/Kir6.2-Q52R ATP-sensitive potassium channel in the presence of PIP2 in the open conformation

Summary for 8TI2

• Entry DOI: 10.2210/pdb8ti2/pdb
• EMDB information: 41277 41278
• Descriptor: ATP-sensitive inward rectifier potassium channel 11, SUR1, [(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho ryl]oxy-propan-2-yl] (8Z)-icosa-5,8,11,14-tetraenoate, ... (8 entities in total)
• Functional Keywords: atp-sensitive potassium channel, katp channel, sur1, kir6.2-q52r, potassium transport, metabolic sensor, diabetes, phospholipid binding, pip2, transport protein
• Biological source: Rattus norvegicus (Norway rat); More
• Total number of polymer chains: 8
• Total formula weight: 902471.99

Authors

Driggers, C.M.,Shyng, S.-L. (deposition date: 2023-07-18, release date: 2024-04-03, Last modification date: 2024-11-20)

Primary citation

Driggers, C.M.,Kuo, Y.Y.,Zhu, P.,ElSheikh, A.,Shyng, S.L.
Structure of an open K ATP channel reveals tandem PIP 2 binding sites mediating the Kir6.2 and SUR1 regulatory interface.
Nat Commun, 15:2502-2502, 2024

PubMed Abstract: ATP-sensitive potassium (K) channels, composed of four pore-lining Kir6.2 subunits and four regulatory sulfonylurea receptor 1 (SUR1) subunits, control insulin secretion in pancreatic β-cells. K channel opening is stimulated by PIP and inhibited by ATP. Mutations that increase channel opening by PIP reduce ATP inhibition and cause neonatal diabetes. Although considerable evidence has implicated a role for PIP in K channel function, previously solved open-channel structures have lacked bound PIP, and mechanisms by which PIP regulates K channels remain unresolved. Here, we report the cryoEM structure of a K channel harboring the neonatal diabetes mutation Kir6.2-Q52R, in the open conformation, bound to amphipathic molecules consistent with natural C18:0/C20:4 long-chain PI(4,5)P at two adjacent binding sites between SUR1 and Kir6.2. The canonical PIP binding site is conserved among PIP-gated Kir channels. The non-canonical PIP binding site forms at the interface of Kir6.2 and SUR1. Functional studies demonstrate both binding sites determine channel activity. Kir6.2 pore opening is associated with a twist of the Kir6.2 cytoplasmic domain and a rotation of the N-terminal transmembrane domain of SUR1, which widens the inhibitory ATP binding pocket to disfavor ATP binding. The open conformation is particularly stabilized by the Kir6.2-Q52R residue through cation-π bonding with SUR1-W51. Together, these results uncover the cooperation between SUR1 and Kir6.2 in PIP binding and gating, explain the antagonistic regulation of K channels by PIP and ATP, and provide a putative mechanism by which Kir6.2-Q52R stabilizes an open channel to cause neonatal diabetes.

PubMed: 38509107
DOI: 10.1038/s41467-024-46751-5

Experimental method

ELECTRON MICROSCOPY (3.28 Å)