AI Article Synopsis
- Sodium-calcium exchanger proteins play a crucial role in maintaining calcium levels in various cell types and are involved in numerous biological and disease processes.
- The study reveals the cryo-EM structure of the human Na/Ca exchanger NCX1.3 with the inhibitor SEA0400, highlighting that the structure is stabilized in an inward-facing state.
- The presence of the exchanger-inhibitory peptide (XIP) and the bound SEA0400 molecule affects specific helices, inhibiting conformational changes necessary for calcium transport and reducing the activity of NCX1.3.
Article 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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| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC10897212 | PMC |
| http://dx.doi.org/10.1038/s44318-023-00013-0 | DOI Listing |
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