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Title | Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400. |
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Journal, issue, pages | EMBO J, Vol. 43, Issue 1, Page 14-31, Year 2024 |
Publish date | Dec 15, 2023 |
Authors | Yanli Dong / Zhuoya Yu / Yue Li / Bo Huang / Qinru Bai / Yiwei Gao / Qihao Chen / Na Li / Lingli He / Yan Zhao / |
PubMed 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 ...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. |
External links | EMBO J / PubMed:38177313 / PubMed Central |
Methods | EM (single particle) |
Resolution | 3.5 Å |
Structure data | EMDB-36465, PDB-8jp0: |
Chemicals | ChemComp-EKY: |
Source |
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Keywords | TRANSPORT PROTEIN / sodium/calcium exchanger / membrane protein |