Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.
EMBO J
; 43(1): 14-31, 2024 Jan.
Article
en En
| MEDLINE
| ID: mdl-38177313
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 TMs1/6 at the outward-facing state, thus hindering conformational transition and promoting inactivation of the transporter. A bound SEA0400 molecule stiffens helix TM2ab and affects conformational rearrangements of TM2ab that are associated with the ion-exchange reaction, thus allosterically attenuating Ca2+-uptake activity of NCX1.3.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Calcio
/
Intercambiador de Sodio-Calcio
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
EMBO J
Año:
2024
Tipo del documento:
Article
País de afiliación:
China