Inositol trisphosphate receptor (InsP3R) is a membrane glycoprotein complex acting as a Ca²⁺ channel activated by inositol trisphosphate (InsP3)^[1]. IP3Rs are intracellular Ca²⁺ channels, predominantly localized to the endoplasmic reticulum (ER) membrane and activated by the binding of IP3 generated in response to external stimulation of G-protein coupled receptors ^[2]. Opening of the IP3Rs results in the rapid release of Ca²⁺ from the ER lumen into the cytoplasm, triggering diverse signaling cascades that regulate physiological processes such as learning, fertilization, gene expression, and apoptosis ^[3]. Dysfunctional IP3Rs cause abnormal Ca²⁺ signaling and are associated with many diseases, including diabetes, cancer, and neurological disorders ^[4].

The 1.2 MDa C4-symmetric assembly consists of an ER-embedded transmembrane domain (TMD) in a domain-swapped 6 transmembrane (6TM) cation channel fold that is capped by a large cytosolic domain (CD) ^[5]. There are three IP3R subtypes (IP3R-1, IP3R-2, and IP3R-3) that share 60–70% sequence identity, form homo- or hetero-tetramers, exhibit different spatial expression profiles, and are involved in different signaling pathways ^[3]. Each IP3R subunit is about 2700 amino acids in length and contains a transmembrane domain (TMD) and a large cytoplasmic region comprising two β-trefold domains (βTF1 and βTF2), three Armadillo repeat domains (ARM1, ARM2, and ARM3), a central linker domain (CLD), a juxtamembrane domain (JD), and a short C-terminal domain (CTD) ^{[6, 7, 8]}.

Ca²⁺ is coordinated by E1882 and E1946 (red sphere) on the ARM3 and the main-chain carboxyl group of T2581 on the JD. H1884 and Q1949 are also close and may interact with Ca²⁺ through water molecules ^[4].

cryo-EM density for ATP in all the structures reveal its key interactions with the protein residues. The adenosine base intercalates into a cavity surrounded by F2156, F2539, I2559, M2565, and W2566 (yellow sphere) near the zinc finger motif and forms hydrogen bonds with the sulfur of C2538, the backbone amide group of F2539, and the carbonyl groups of H2563 and I2559. The phosphate moieties interact with K2152, K2560, and N2564 ^[4].

The mutant R568Q (black sphere) exhibited lower affinity for (1,4,5)IP3 and a different binding specificity for various inositol phosphates, suggesting that Arg-568 is involved in not only high affinity binding with (1,4,5)IP3 but also determination of binding specificity. Therefore, Arg-568 may be involved in recognition of the functional group at the equatorial position-1 of the inositol ring, since R568Q recognizes (4,5)IP2 and (2,4,5)IP3 with higher affinity but (1,4,5)IP3 and (1,3,4,5)IP4 with lower affinity than the wild type ^[9].