Structural identification of vasodilator binding sites on the SUR2 subunit

Area of Science:

• Biochemistry
• Structural Biology
• Pharmacology

Background:

• ATP-sensitive potassium channels (K_ATP), formed by Kir6 and SUR subunits, link cellular metabolism to electrical signaling.
• K_ATP openers, a class of drugs, activate SUR2-containing channels, causing hyperpolarization and vasodilation, suggesting therapeutic potential for cardiovascular diseases.

Purpose of the Study:

• To elucidate the binding site and activation mechanism of K_ATP openers on SUR2 subunits.
• To present high-resolution structural insights into K_ATP channel activation by specific SUR2 ligands.

Main Methods:

• Cryo-electron microscopy (cryo-EM) was used to determine the structures of SUR2A and SUR2B subunits.
• Structures were obtained in complex with Mg-nucleotides and two distinct K_ATP openers: P1075 and levcromakalim.

Main Results:

• Identified a common binding site for P1075 and levcromakalim within the transmembrane domain (TMD) of the SUR2 subunit.
• Observed that these K_ATP openers bind between TMD1 and TMD2, interacting with multiple transmembrane helices (TM10, TM11, TM12, TM14, TM17).
• Demonstrated that K_ATP openers synergize with Mg-nucleotides to stabilize SUR2 in an NBD-dimerized occluded state, thereby activating the channel.

Conclusions:

• The study reveals the precise structural basis for K_ATP opener binding and activation of SUR2-containing channels.
• These findings provide a molecular understanding of how K_ATP openers modulate channel activity, paving the way for rational drug design for cardiovascular conditions.