Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.

ABSTRACT: Sodium-calcium exchanger proteins influence calcium homeostasis in many cell types and participate in a wide range of physiological and pathological processes. Here, we elucidate the cryo-EM structure of the human Na⁺/Ca²⁺ exchanger NCX1.3 in the presence of a specific inhibitor, SEA0400. Conserved ion-coordinating residues are exposed on the cytoplasmic face of NCX1.3, indicating that the observed structure is stabilized in an inward-facing conformation. We show how regulatory calcium-binding domains (CBDs) assemble with the ion-translocation transmembrane domain (TMD). The exchanger-inhibitory peptide (XIP) is trapped within a groove between the TMD and CBD2 and predicted to clash with gating helices TMs^1/6 at the outward-facing state, thus hindering conf

SUBMITTER: Dong Y 

PROVIDER: S-EPMC10897212 | biostudies-literature | 2024 Jan

REPOSITORIES: biostudies-literature