8JP0

structure of human sodium-calciumexchanger NCX1

Summary for 8JP0

• Entry DOI: 10.2210/pdb8jp0/pdb
• EMDB information: 36465
• Descriptor: Sodium/calcium exchanger 1, 2-{4-[(2,5-difluorophenyl)methoxy]phenoxy}-5-ethoxyaniline (2 entities in total)
• Functional Keywords: sodium/calcium exchanger, membrane protein, transport protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 105165.64

Authors

Dong, Y.,Zhao, Y. (deposition date: 2023-06-09, release date: 2024-01-03, Last modification date: 2024-01-24)

Primary citation

Dong, Y.,Yu, Z.,Li, Y.,Huang, B.,Bai, Q.,Gao, Y.,Chen, Q.,Li, N.,He, L.,Zhao, Y.
Structural insight into the allosteric inhibition of human sodium-calcium exchanger NCX1 by XIP and SEA0400.
Embo J., 43:14-31, 2024

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 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.

PubMed: 38177313
DOI: 10.1038/s44318-023-00013-0

Experimental method

ELECTRON MICROSCOPY (3.5 Å)