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| Title | Cryo-EM insights into isoform-specific properties of the IPR2 channel. |
|---|---|
| Journal, issue, pages | Nat Commun, Vol. 17, Issue 1, Year 2026 |
| Publish date | Jul 22, 2026 |
Authors | Mariah R Baker / Xiaoxuan Lin / Guizhen Fan / Ariel Martinez-Chavez / Larry E Wagner / Sundeep Malik / Tyler Allison / Briar Bell / Alexander B Seryshev / Julio Cordero-Morales / Matthew L Baker / David I Yule / Irina I Serysheva / ![]() |
| 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 ...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. |
External links | Nat Commun / PubMed:42637755 / PubMed Central |
| Methods | EM (single particle) |
| Resolution | 2.95 - 3.64 Å |
| Structure data | ![]() EMDB-76249: Apo-IP3R2 Local Refinement of Ligand Binding Domains ![]() EMDB-76250: Apo-IP3R2 Local Refinement of ARM1-HD Domains ![]() EMDB-76251: Apo-IP3R2 Local Refinement of ARM2 Domain ![]() EMDB-76252: Apo-IP3R2 Local Refinement of ARM3-ILD-LNK domains ![]() EMDB-76253: Apo-IP3R2 Local Refinement of TM domains ![]() EMDB-76254: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of Ligand Binding Domains ![]() EMDB-76255: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of ARM1-HD domains ![]() EMDB-76256: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of TM domains ![]() EMDB-76257: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of ARM2 domains ![]() EMDB-76258: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of ARM3-ILD-LNK domains ![]() EMDB-76259: Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptors (IP3R2) in the Apo-state (composite map) EMDB-76260, PDB-12ad: ![]() EMDB-76262: Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptor (IP3R2)in the presence of IP3/Ca2+/ATP (Composite map) EMDB-76264, PDB-12ai: |
| Chemicals | ![]() ChemComp-ZN: ![]() ChemComp-PLX: ![]() ChemComp-ATP: ![]() ChemComp-I3P: ![]() ChemComp-CA: |
| Source |
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Keywords | MEMBRANE PROTEIN / ion channel |
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