TY - JOUR T1 - Cryo-EM structure of the ATP-sensitive potassium channel illuminates mechanisms of assembly and gating JF - bioRxiv DO - 10.1101/094649 SP - 094649 AU - Gregory M. Martin AU - Craig Yoshioka AU - Emily A. Rex AU - Jonathan F. Fay AU - Qing Xie AU - Matt R. Whorton AU - James Z. Chen AU - Show-Ling Shyng Y1 - 2016/01/01 UR - http://biorxiv.org/content/early/2016/12/16/094649.abstract N2 - ATP-sensitive potassium (KATP) channels are metabolic sensors that couple cell energetics to membrane excitability. In pancreatic β-cells, channels formed by SUR1 and Kir6.2 regulate insulin secretion and are the targets of antidiabetic sulfonylureas. Here, we used cryo-EM to elucidate structural basis of channel assembly and gating. The structure, determined in the presence of ATP and the sulfonylurea glibenclamide, at ~6Å resolution reveals a closed Kir6.2 tetrameric core with four peripheral SUR1s each anchored to a Kir6.2 by its N-terminal transmembrane domain (TMD0). Intricate interactions between TMD0, the loop following TMD0, and Kir6.2 near the proposed PIP2 binding site, and where ATP density is observed, suggest SUR1 may contribute to ATP and PIP2 binding to enhance Kir6.2 sensitivity to both. The SUR1-ABC core is found in an unusual inward-facing conformation whereby the two nucleotide binding domains are misaligned along a two-fold symmetry axis, revealing a possible mechanism by which glibenclamide inhibits channel activity. ER -