Scientists at the Icahn School of Medicine have revealed the structure of NBCn2, a brain protein linked to epilepsy and autism spectrum disorder. Their work, published in Nature Communications on August 4, 2026, also produced the first compounds that can block the protein’s activity, offering a new molecular tool for future research.
The protein helps regulate the acid-base balance inside brain cells, a process that is essential for keeping neuronal signaling stable. Genetic variants that alter NBCn2 have been associated with several neurological conditions, yet scientists previously knew little about how the protein works or whether it could be targeted by drugs.
Uncovering the protein’s structure
Using cryo-electron microscopy, the research team captured detailed images of NBCn2 at near-atomic resolution. The technique allowed them to visualize how the transporter moves both sodium and carbonate ions across the cell membrane, providing the first clear picture of its three-dimensional shape.
“This protein had been largely overlooked, despite clear links to serious neurological disorders,” said Daniel Wacker, a senior author of the paper. The investigators set out to map the molecular mechanism of NBCn2 and to assess whether the structure could reveal points for therapeutic intervention.
Designing inhibitory compounds
The structural information served as a blueprint for creating molecules that could block NBCn2. In a series of tests performed with mouse brain cells and isolated brain tissue, one of the newly synthesized compounds noticeably reduced the electrical signaling that normally occurs between neurons.
“For the first time, we were able to pharmacologically control this transporter and directly observe effects on neuronal activity,” explained Bin Zhang, another senior author. This achievement supplies a practical starting point for probing how NBCn2 influences brain function and disease.
The project also incorporated extensive computer modeling, AI-based predictions, and a broad virtual screening of thousands of chemical candidates. Promising hits from this in-silico work were then synthesized, introduced into cells, and evaluated with electrophysiological recording techniques to confirm their impact on ion transport.
Researchers found that NBCn2 binds sodium and carbonate ions in a pattern that differs from that of related transporters. “One surprising finding was that NBCn2 uses a substrate-binding mechanism we had not seen before,” noted Shifan Yang, the study’s first author. This distinctive mode of interaction could be exploited to design drugs that target NBCn2 without affecting other proteins.
Implications for epilepsy and beyond
“These compounds are not drugs,” clarified Avner Schlessinger, a co-author. “Much more work is needed to improve their potency and selectivity and to test them in complex disease models before therapeutic conclusions can be drawn.”
