Ligand-mediated Structural Dynamics of a Mammalian Pancreatic KATP Channel

Mechanistic insights on KATP channel regulation from cryo-EM structures

“…In addition to residues from Kir6.2, K205 of SUR1 in the L0 loop, immediately following TMD0, has its side chain pointed toward the β- and γ-phosphates of ATP in the cryo-EM structures ( Ding et al, 2019 ; Sung et al, 2022 ; Fig. 3 ).…”

“…As discussed in detail in the Pharmacological modulators of K ATP channels section, cryo-EM structures of K ATP channels formed by separate SUR1 and Kir6.2 proteins bound to pharmacological inhibitors and/or ATP have uncovered the density of Kir6.2 N-terminal peptide (approximately the first 30 amino acids; referred to as KNtp) in the vestibule between the two halves of the SUR1 ABC core module ( Martin et al, 2019 ; Sung et al, 2022 ; Fig. 4 A ).…”

“…Early work has shown that TMD0 from SUR1 is sufficient to confer the high open probability of Kir6.2/SUR1 channels ( Babenko and Bryan, 2003 ; Chan et al, 2003 ); however, the underlying structural mechanism has remained unclear. Despite the controversy on PIP 2 and K ATP channel interactions discussed above, a recent study of K ATP cryo-EM structures did provide evidence that SUR1 enhances K ATP channel sensitivity to phospholipids/PIP 2 by contributing to phospholipid binding ( Sung et al, 2022 ). In a structure of the Kir6.2/SUR1 channel bound to repaglinide (Repa) and ATP, a lysine residue located in ICL2 of the SUR1–TMD0 domain (K134) has its side chain directed toward the head group of the lipid density in the proposed Kir6.2 PIP 2 binding pocket ( Fig.…”

“…(B) Inside-out patch-clamp recordings comparing the response of WT and SUR1-K134A mutant channels to PIP 2 (adapted from Fig. 5 in Sung et al, 2022 ). Top: The WT channel showed a characteristic opening response to PIP 2 exposure, and closure upon exposure to ATP.…”

“…Since 2017, a flurry of K ATP structures of wild-type or mutant channels, formed by individual Kir6 and SUR proteins or SUR-Kir6 fusion containing different lengths of linkers, in various ligand conditions have been reported using single-particle cryo-EM. The majority of these structures are of the pancreatic K ATP subtype ( Ding et al, 2019 ; Lee et al, 2017 ; Li et al, 2017 ; Martin et al, 2017a ; Martin et al, 2019 ; Martin et al, 2017b ; Sung et al, 2022 ; Sung et al, 2021 ; Wang et al, 2022 ; Wu et al, 2018 ; Zhao and MacKinnon, 2021 ); only one study has reported structures of the vascular K ATP channel ( Sung et al, 2021 ). These studies have revealed the overall architecture of the channel, the Kir6 tetramer in closed or open conformations, and SUR in inactive NBDs’ separate or activated NBDs-dimerized conformations, as well as the binding sites for pharmacological inhibitors and activators ( Fig.…”