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

  • EMBO J. 2024 Jan;43(1):14-31. doi: 10.1038/s44318-023-00013-0.
Yanli Dong  #  1 ,  Zhuoya Yu  #  1  2  3 ,  Yue Li  #  1  2  3 ,  Bo Huang  4 ,  Qinru Bai  1  2  3 ,  Yiwei Gao  1  2  3 ,  Qihao Chen  1  2  3 ,  Na Li  5 ,  Lingli He  1 ,  Yan Zhao  6  7  8
Affiliations
  • 1. Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China.
  • 2. State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China.
  • 3. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China.
  • 4. Beijing StoneWise Technology Co Ltd., 15 Haidian street, Haidian district, Beijing, China.
  • 5. Heart Center and Beijing Key Laboratory of Hypertension, Beijing Chaoyang Hospital, Capital Medical University, Beijing, 100020, China.
  • 6. Key Laboratory of Biomacromolecules (CAS), National Laboratory of Biomacromolecules, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, 100101, China. [email protected].
  • 7. State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing, 100101, China. [email protected].
  • 8. College of Life Sciences, University of Chinese Academy of Sciences, Beijing, 100049, China. [email protected].
  • # Contributed equally.
PMID: 38177313 DOI: 10.1038/s44318-023-00013-0
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.

Keywords
Allosteric Inhibition; Calcium Homeostasis; Exchanger Inhibitory Peptide (XIP); SEA0400; Sodium-calcium Exchanger.
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