Work

Substrate coupling and inhibition in human Na+-dependent Cl−/HCO3− exchanger NCBE (SLC4A10)

Year: 2026

Type: article

Abstract: Maintaining pH homeostasis is essential for neuronal excitability and for regulating cerebrospinal fluid (CSF). The Na + -dependent Cl − /HCO 3 − 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 HCO 3 − , 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 validate ion coordination and inhibitor effects. Comparison of cryo-EM structures with an AlphaFold3 inward-facing model supports an elevator-like mechanism and completes the conformational cycle of Na + -coupled HCO 3 − transporters. Together, these findings define the structural basis of NCBE and provide a framework for understanding ion coupling and pharmacological modulation within the SLC4 family.

Source: Nature Communications

DOI: 10.1038/s41467-026-77504-1