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TitleCryo-EM insights into isoform-specific properties of the IPR2 channel.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateJul 22, 2026
AuthorsMariah 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 AbstractCalcium 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 linksNat Commun / PubMed:42637755 / PubMed Central
MethodsEM (single particle)
Resolution2.95 - 3.64 Å
Structure data

EMDB-76249: Apo-IP3R2 Local Refinement of Ligand Binding Domains
Method: EM (single particle) / Resolution: 2.95 Å

EMDB-76250: Apo-IP3R2 Local Refinement of ARM1-HD Domains
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-76251: Apo-IP3R2 Local Refinement of ARM2 Domain
Method: EM (single particle) / Resolution: 3.57 Å

EMDB-76252: Apo-IP3R2 Local Refinement of ARM3-ILD-LNK domains
Method: EM (single particle) / Resolution: 2.98 Å

EMDB-76253: Apo-IP3R2 Local Refinement of TM domains
Method: EM (single particle) / Resolution: 2.99 Å

EMDB-76254: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of Ligand Binding Domains
Method: EM (single particle) / Resolution: 3.57 Å

EMDB-76255: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of ARM1-HD domains
Method: EM (single particle) / Resolution: 3.62 Å

EMDB-76256: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of TM domains
Method: EM (single particle) / Resolution: 3.64 Å

EMDB-76257: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of ARM2 domains
Method: EM (single particle) / Resolution: 3.23 Å

EMDB-76258: IP3R2 (+IP3/Ca2+/ATP) Local Refinement of ARM3-ILD-LNK domains
Method: EM (single particle) / Resolution: 3.34 Å

EMDB-76259: Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptors (IP3R2) in the Apo-state (composite map)
Method: EM (single particle) / Resolution: 3.2 Å

EMDB-76260, PDB-12ad:
Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptors (IP3R2) in the Apo-state
Method: EM (single particle) / Resolution: 3.32 Å

EMDB-76262: Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptor (IP3R2)in the presence of IP3/Ca2+/ATP (Composite map)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-76264, PDB-12ai:
Structure of mammalian Type 2 Inositol 1,4,5-trisphosphate receptor (IP3R2) in the presence of IP3/Ca2+/ATP
Method: EM (single particle) / Resolution: 3.64 Å

Chemicals

ChemComp-ZN:
Unknown entry

ChemComp-PLX:
(9R,11S)-9-({[(1S)-1-HYDROXYHEXADECYL]OXY}METHYL)-2,2-DIMETHYL-5,7,10-TRIOXA-2LAMBDA~5~-AZA-6LAMBDA~5~-PHOSPHAOCTACOSANE-6,6,11-TRIOL / phospholipid*YM

ChemComp-ATP:
ADENOSINE-5'-TRIPHOSPHATE / ATP, energy-carrying molecule*YM

ChemComp-I3P:
D-MYO-INOSITOL-1,4,5-TRIPHOSPHATE

ChemComp-CA:
Unknown entry

Source
  • mus musculus (house mouse)
KeywordsMEMBRANE PROTEIN / ion channel

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