Substrate coupling and inhibition in human Na+-dependent Cl−/HCO3− exchanger NCBE (SLC4A10)
Abstract
Maintaining pH homoeostasis is essential for neuronal excitability and for regulating cerebrospinal fluid (CSF). The Na⁺-dependent Cl⁻/HCO₃⁻ exchanger, NCBE (SLC4A10), abundant in the choroid plexus, contributes to CSF pH control by mediating bicarbonate flux, yet its molecular mechanism has remained unclear. Here we report cryo-EM structures of human NCBE in multiple functional states, revealing conserved binding sites for Na⁺, Cl⁻, and HCO₃⁻, as well as an unexpected K⁺ site indicating relaxed cation selectivity. The inhibitor DIDS binds above the substrate cavity, locking NCBE in an outward-facing conformation and defining a subfamily-selective inhibitory mechanism. Functional assays and molecular dynamics simulations support the coordination of ions and the inhibitory effects. Comparison with an AlphaFold3-predicted inward-facing model suggests an elevator-like transport mechanism and delineates the conformational transitions in Na⁺-dependent HCO₃⁻ transporters. Together, these findings establish a structural framework for NCBE and offer insights into ion coupling and pharmacological modulation within the SLC4 family.
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BibTeX
@article{sun2026substrate,
title = {{Substrate coupling and inhibition in human Na+-dependent Cl−/HCO3− exchanger NCBE (SLC4A10)}},
author = {Peixin Sun and Xinmin Wang and Yang Huang and Jinlun Kylian Zhang and Xurui Shen and Anqi Dong and Shiliang Wang and Xiaojun Guo and Guoming Shi and Jing Ding and Yudan Chi and Hanting Yang},
journal = {Nature Communications},
year = {2026},
month = oct,
doi = {10.1038/s41467-026-77504-1},
url = {https://www.nature.com/articles/s41467-026-77504-1},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Substrate coupling and inhibition in human Na+-dependent Cl−/HCO3− exchanger NCBE (SLC4A10)
AU - Peixin Sun
AU - Xinmin Wang
AU - Yang Huang
AU - Jinlun Kylian Zhang
AU - Xurui Shen
AU - Anqi Dong
AU - Shiliang Wang
AU - Xiaojun Guo
AU - Guoming Shi
AU - Jing Ding
AU - Yudan Chi
AU - Hanting Yang
PY - 2026
DA - 2026/10/01
JO - Nature Communications
DO - 10.1038/s41467-026-77504-1
UR - https://www.nature.com/articles/s41467-026-77504-1
AB - Maintaining pH homoeostasis is essential for neuronal excitability and for regulating cerebrospinal fluid (CSF). The Na⁺-dependent Cl⁻/HCO₃⁻ exchanger, NCBE (SLC4A10), abundant in the choroid plexus, contributes to CSF pH control by mediating bicarbonate flux, yet its molecular mechanism has remained unclear. Here we report cryo-EM structures of human NCBE in multiple functional states, revealing conserved binding sites for Na⁺, Cl⁻, and HCO₃⁻, as well as an unexpected K⁺ site indicating relaxed cation selectivity. The inhibitor DIDS binds above the substrate cavity, locking NCBE in an outward-facing conformation and defining a subfamily-selective inhibitory mechanism. Functional assays and molecular dynamics simulations support the coordination of ions and the inhibitory effects. Comparison with an AlphaFold3-predicted inward-facing model suggests an elevator-like transport mechanism and delineates the conformational transitions in Na⁺-dependent HCO₃⁻ transporters. Together, these findings establish a structural framework for NCBE and offer insights into ion coupling and pharmacological modulation within the SLC4 family.
SN - 2041-1723
ER -