Structural Insight into the Allosteric Inhibition of Human Sodium-calcium Exchanger NCX1 by XIP and SEA0400

Overview

Journal EMBO J

Specialties Biotechnology
Molecular Biology

Date 2024 Jan 4

PMID 38177313

Authors

Yanli Dong

Zhuoya Yu

Yue Li

Bo Huang

Qinru Bai

Yiwei Gao

Qihao Chen

Na Li

Lingli He

Yan Zhao

Affiliations

Soon will be listed here.

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/Ca 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 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 Ca-uptake activity of NCX1.3.

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