Cryo-electron microscopy structures and progress toward a dynamic understanding of K_ATP channels

Area of Science:

• Molecular biology
• Cellular metabolism
• Ion channel function

Background:

• Adenosine triphosphate (ATP)-sensitive K⁺ (K_ATP) channels are crucial metabolic sensors.
• These hetero-octameric channels comprise Kir and sulfonylurea receptor (SUR) subunits.
• K_ATP channels link cellular metabolism to physiological responses like insulin secretion.

Purpose of the Study:

• To discuss recent cryo-electron microscopy (cryo-EM) structures of the pancreatic K_ATP channel (Kir6.2/SUR1).
• To elucidate the mechanisms of excitatory and inhibitory ligand binding to K_ATP channels.
• To propose a model for K_ATP channel activation via SUR ligand-binding domains.

Main Methods:

• Analysis of single-particle cryo-electron microscopy (cryo-EM) structures.
• Investigation of K_ATP channel assembly and gating mechanisms.
• Examination of adenine nucleotide binding sites on Kir and SUR subunits.

Main Results:

• Near-atomic resolution cryo-EM structures provide detailed insights into K_ATP channel architecture.
• Identified distinct intracellular adenine nucleotide binding sites on Kir and SUR subunits.
• Elucidated mechanisms of channel inhibition (Kir-bound ATP/ADP) and excitation (SUR-bound Mg nucleotides).

Conclusions:

• Recent structural data offer a detailed picture of ligand binding and gating in K_ATP channels.
• Proposed mechanism for signal transduction from SUR ligand-binding domains to the channel pore.
• Structural understanding facilitates insights into metabolic regulation of insulin secretion.