12AI

Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptor (IP3R2) in the presence of IP3/Ca2+/ATP

Summary for 12AI

• Entry DOI: 10.2210/pdb12ai/pdb
• EMDB information: 76262 76264
• Descriptor: Inositol 1,4,5-trisphosphate-gated calcium channel ITPR2, ZINC ION, ADENOSINE-5'-TRIPHOSPHATE, ... (6 entities in total)
• Functional Keywords: ion channel, membrane protein
• Biological source: Mus musculus (house mouse)
• Total number of polymer chains: 4
• Total formula weight: 1238618.46

Authors

Serysheva, I.I.,Baker, M.R.,Fan, G. (deposition date: 2026-03-23, release date: 2026-07-29, Last modification date: 2026-09-09)

Primary citation

Baker, M.R.,Lin, X.,Fan, G.,Martinez-Chavez, A.,Wagner, L.E.,Malik, S.,Allison, T.,Bell, B.,Seryshev, A.B.,Cordero-Morales, J.,Baker, M.L.,Yule, D.I.,Serysheva, I.I.
Cryo-EM insights into isoform-specific properties of the IP 3 R2 channel.
Nat Commun, 17:-, 2026

PubMed Abstract: Calcium release through inositol 1,4,5-trisphosphate receptors (IPRs) is a fundamental signaling mechanism that regulates diverse cellular processes. Among the three mammalian IPR isoforms, IPR2 is widely expressed, yet its structural basis for activation and regulation remains unclear. Here, we report cryo-EM structures of mammalian IPR2 in ligand-free (closed) and CaIP/ATP-bound (activated) states at 3.3 Å and 3.6 Å resolution, respectively. These structures define the architecture of IPR2 and reveal conformational transitions associated with channel activation. Although the IP-binding pocket is conserved, subtype-specific differences in IP affinity likely arise from conformational dynamics of the regulatory ARM2 domain. Comparative analyses of IPR isoforms identify subtype-specific allosteric networks and domain motions that underlie differential regulation. We further define the ATP-binding site and, through mutagenesis and electrophysiology, establish the structural basis for ATP modulation of channel activity. Together, these findings reveal mechanisms of IPR2 activation and subtype-specific regulation, providing a framework for understanding isoform-dependent Ca signaling.

PubMed: 42637755
DOI: 10.1038/s41467-026-75806-y

Experimental method

ELECTRON MICROSCOPY (3.64 Å)