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TitleStructural mechanisms of PIP activation and SEA0400 inhibition in human cardiac sodium-calcium exchanger NCX1.
Journal, issue, pagesElife, Vol. 14, Year 2025
Publish dateMay 28, 2025
AuthorsJing Xue / Weizhong Zeng / Scott John / Nicole Attiq / Michela Ottolia / Youxing Jiang /
PubMed AbstractNa/Ca exchangers (NCXs) transport Ca across the plasma membrane in exchange for Na and play a vital role in maintaining cellular Ca homeostasis. Our previous structural study of human cardiac NCX1 ...Na/Ca exchangers (NCXs) transport Ca across the plasma membrane in exchange for Na and play a vital role in maintaining cellular Ca homeostasis. Our previous structural study of human cardiac NCX1 (HsNCX1) reveals the overall architecture of the eukaryotic exchanger and the formation of the inactivation assembly by the intracellular regulatory domain that underlies the cytosolic Na-dependent inactivation and Ca activation of NCX1. Here, we present the cryo-EM structures of HsNCX1 in complex with a physiological activator phosphatidylinositol 4,5-bisphosphate (PIP), or pharmacological inhibitor SEA0400, that enhances the inactivation of the exchanger. We demonstrate that PIP binding stimulates NCX1 activity by inducing a conformational change at the interface between the transmembrane (TM) and cytosolic domains that destabilizes the inactivation assembly. In contrast, SEA0400 binding in the TM domain of NCX1 stabilizes the exchanger in an inward-facing conformation that facilitates the formation of the inactivation assembly, thereby promoting the Na-dependent inactivation of NCX1. Thus, this study reveals the structural basis of PIP activation and SEA0400 inhibition of NCX1 and provides some mechanistic understandings of cellular regulation and pharmacology of NCX family proteins.
External linksElife / PubMed:40433952 / PubMed Central
MethodsEM (single particle)
Resolution2.9 - 3.5 Å
Structure data

40456

8sgi

EMDB-40456, PDB-8sgi:
Cryo-EM structure of human NCX1 in complex with SEA0400
Method: EM (single particle) / Resolution: 2.9 Å

60921

9iv8

EMDB-60921, PDB-9iv8:
Cryo-EM structure of human NCX1 in PIP2 diC8 bound state
Method: EM (single particle) / Resolution: 3.5 Å

Chemicals

ChemComp-EKY:
2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline

ChemComp-CA:
Unknown entry

ChemComp-NA:
Unknown entry

ChemComp-HOH:
WATER

ChemComp-PIO:
[(2R)-2-octanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phosphoryl]oxy-propyl] octanoate

Source
  • homo sapiens (human)
  • mus musculus (house mouse)
KeywordsTRANSPORT PROTEIN / Na/Ca exchanger / sodium calcium exchanger

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