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TitleConformational landscape and ligand-dependent clustering of the human type 2 IP receptor.
Journal, issue, pagesNat Commun, Vol. 17, Issue 1, Year 2026
Publish dateJun 19, 2026
AuthorsCaifeng Liu / Yu-Jing Lan / Max G Kushner / Qingyu Tang / Erkan Karakas /
PubMed AbstractInositol 1,4,5-trisphosphate (IP) receptors (IPRs) are tetrameric ER Ca channels that shape intracellular Ca signaling in response to IP, regulating diverse physiological processes. The structural ...Inositol 1,4,5-trisphosphate (IP) receptors (IPRs) are tetrameric ER Ca channels that shape intracellular Ca signaling in response to IP, regulating diverse physiological processes. The structural basis for subtype-specific regulation among the three subtypes (IPR-1-3) remains incompletely understood due to the lack of IPR-2 structures. Here, we report cryo-electron microscopy (cryo-EM) structures of human IPR-2 in distinct conformations in the presence and absence of IP, Ca, and ATP. These structures define the conformational landscape of IPR-2, delineate ligand-binding interactions, and reveal shared architectural features alongside isoform-specific differences. We also resolve ligand-dependent IPR-2 assemblies, identifying a conformation-dependent inter-channel interface. Live-cell imaging demonstrates that IPR-2 undergoes clustering following ligand-induced Ca release, and disruption of this interface selectively abolishes clustering without impairing channel activity. Together, these findings provide a structural framework for human IPR-2 and establish a mechanism linking ligand-dependent conformational changes to inter-channel interactions and post-activation cellular clustering.
External linksNat Commun / PubMed:42315508 / PubMed Central
MethodsEM (single particle)
Resolution2.71 - 4.47 Å
Structure data

EMDB-73048: Human type 2 IP3 receptor apo state consensus map
Method: EM (single particle) / Resolution: 2.95 Å

EMDB-73049: Human type 2 IP3 receptor apo state ligand binding domain (LBD) local refinement
Method: EM (single particle) / Resolution: 2.72 Å

EMDB-73050: Human type 2 IP3 receptor apo state central linker domain (CLD) local refinement
Method: EM (single particle) / Resolution: 2.88 Å

EMDB-73051: Human type 2 IP3 receptor apo state ARM2 domain local refinement
Method: EM (single particle) / Resolution: 3.21 Å

EMDB-73052: Human type 2 IP3 receptor apo state ARM3-JD domain local refinement
Method: EM (single particle) / Resolution: 2.71 Å

EMDB-73053: Human type 2 IP3 receptor apo state transmembrane domain (TMD) local refinement
Method: EM (single particle) / Resolution: 2.78 Å

EMDB-73054, PDB-9ykk:
Human type 2 IP3 receptor in apo state
Method: EM (single particle) / Resolution: 2.95 Å

EMDB-73061: IP3/ATP bound human type 2 IP3 receptor in the resting state - Consensus map
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-73062: Local refined ligand-binding domain (LBD) of IP3/ATP bound human type 2 IP3 receptor in the resting state
Method: EM (single particle) / Resolution: 3.0 Å

EMDB-73063: Local refined central linker domain (CLD) of IP3/ATP bound human type 2 IP3 receptor in the resting state
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-73064: Local refined ARM2 domain of IP3/ATP bound human type 2 IP3 receptor in the resting state
Method: EM (single particle) / Resolution: 3.73 Å

EMDB-73065: Local refined ARM3-JD domains of IP3/ATP bound human type 2 IP3 receptor in the resting state
Method: EM (single particle) / Resolution: 3.06 Å

EMDB-73066: Local refined transmembrane domain (TMD) of IP3/ATP bound human type 2 IP3 receptor in the resting state
Method: EM (single particle) / Resolution: 3.23 Å

EMDB-73067, PDB-9yky:
IP3/ATP-bound human type 2 IP3 receptor in the resting state
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-73082: IP3/ATP-bound human type 2 IP3 receptor in the preactivated state - Consensus map
Method: EM (single particle) / Resolution: 3.33 Å

EMDB-73083: Local refined ligand-binding domain (LBD) of IP3/ATP-bound human type 2 IP3 receptor in the preactivated state
Method: EM (single particle) / Resolution: 3.05 Å

EMDB-73084: Local refined central linker domain (CLD) of IP3/ATP-bound human type 2 IP3 receptor in the preactivated state
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-73085: Local refined ARM2 domain of IP3/ATP-bound human type 2 IP3 receptor in the preactivated state
Method: EM (single particle) / Resolution: 3.24 Å

EMDB-73086: Local refined ARM3-JD domains of IP3/ATP-bound human type 2 IP3 receptor in the preactivated state
Method: EM (single particle) / Resolution: 3.03 Å

EMDB-73087: Local refined transmembrane domain (TMD) of IP3/ATP-bound human type 2 IP3 receptor in the preactivated state
Method: EM (single particle) / Resolution: 2.91 Å

EMDB-73088, PDB-9yli:
IP3/ATP-bound human type 2 IP3 receptor in the preactivated state
Method: EM (single particle) / Resolution: 3.33 Å

EMDB-73111: Human type 2 IP3 receptor in the inactive-like state (IP3/ATP) Consensus Map
Method: EM (single particle) / Resolution: 3.14 Å

EMDB-73112: Local refined ligand-binding domain (LBD, chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.33 Å

EMDB-73113: Local refined central linker domain (CLD, chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.08 Å

EMDB-73114: Local refined ARM2 (chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-73115: Local refined ARM3-JD (chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 2.86 Å

EMDB-73116: Local refined central linker domain (CLD, chain B) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.31 Å

EMDB-73117: Local refined ARM2 (chain B) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.47 Å

EMDB-73118: Local refined ARM3-JD (chain B) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 2.92 Å

EMDB-73119: Local refined ARM3-JD (chain C) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.01 Å

EMDB-73120: Local refined JD (chain D) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP
Method: EM (single particle) / Resolution: 3.12 Å

EMDB-73121: Local refined transmembrane domain (TMD) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 2.88 Å

EMDB-73129, PDB-9ymz:
Human type 2 IP3 receptor in the inactive-like state (IP3/ATP)
Method: EM (single particle) / Resolution: 3.14 Å

EMDB-73198: Human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+) Consensus Map
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-73199: Local refined ligand-binding domain (LBD, chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.89 Å

EMDB-73201: Local refined central linker domain (CLD, chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.4 Å

EMDB-73202: Local refined ARM2 (chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.75 Å

EMDB-73203: Local refined ARM3-JD (chain A) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.16 Å

EMDB-73204: Local refined central linker domain (CLD, chain B) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.66 Å

EMDB-73205: Local refined ARM2 (chain B) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.98 Å

EMDB-73206: Local refined ARM3-JD (chain B) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.22 Å

EMDB-73207: Local refined ARM3-JD (chain C) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.68 Å

EMDB-73208: Local refined JD (chain D) of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.45 Å

EMDB-73209: Local refined JD and TMD of human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.15 Å

EMDB-73210, PDB-9ynk:
Human type 2 IP3 receptor in the inactive-like state (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.42 Å

EMDB-73212: Human type 2 IP3 receptor dimer (IP3/ATP/Ca2+) Consensus Map
Method: EM (single particle) / Resolution: 4.06 Å

EMDB-73213: Local refined dimerization interface of human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.54 Å

EMDB-73214: Local refined central linker domain (CLD, chain A) of human type 2 IP3 receptor in dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.85 Å

EMDB-73215: Local refined ARM2 (chain A) of human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 4.0 Å

EMDB-73216: Local refined ARM3-JD (chain A) of human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 3.73 Å

EMDB-73217: Local refined N-terminal domain (NTD, chain B) of human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 4.23 Å

EMDB-73218: Local refined JD and TMD of human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 4.06 Å

EMDB-73219, PDB-9yno:
Human type 2 IP3 receptor dimer (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 4.06 Å

EMDB-73222: Human type 2 IP3 receptor dimer complete map (IP3/ATP/Ca2+)
Method: EM (single particle) / Resolution: 4.4 Å

EMDB-73223: Human type 2 IP3 receptor in the intermediate state 3 (IP3/ATP)
Method: EM (single particle) / Resolution: 4.47 Å

EMDB-73224: Human type 2 IP3 receptor in the intermediate state 4 (IP3/ATP)
Method: EM (single particle) / Resolution: 4.17 Å

EMDB-73225: Human type 2 IP3 receptor in the inactive-like state (ligand-free)
Method: EM (single particle) / Resolution: 3.99 Å

Chemicals

ChemComp-ZN:
Unknown entry

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

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

ChemComp-HOH:
WATER

ChemComp-CA:
Unknown entry

Source
  • homo sapiens (human)
KeywordsTRANSPORT PROTEIN / Inositol 1 / 4 / 5-triphosphate / IP3 / receptor / calcium channel / type-2 / IP3R / IP3R-2 / ITPR2

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