Structural features of the Orai channel. (A) Top down view of the crystal structure of Drosophila Orai (PDB ID: 4HKR), showing a hexameric channel with concentric layers of transmembrane domains (TMs) surrounding the pore-lining TM1 helices (Hou et al., 2012). TMs 1–4 and the C-terminal extensions are shown in blue, green, red, orange, and yellow, respectively. (B) The peripheral STIM1 binding sites formed by pairs of neighboring C-terminal extensions are highlighted in blue, with residue I316 (human Orai1 L273) shown in red sticks. (C) TMs 2 and 3, colored in blue, form an interlocked ring situated in between TM1 and TM4. This cage of helices may play a key role in enforcing cooperativity in transmitting the STIM1 binding signal from the C termini of different Orai1 subunits to the pore. Residue F171 (human Orai1 F99), which forms the dynamically regulated part of the hydrophobic gate in the pore, is depicted in gray sticks.