9MJO

Cryo-EM structure of human NBCn2 bound to Carbonate

Summary for 9MJO

• Entry DOI: 10.2210/pdb9mjo/pdb
• EMDB information: 48318
• Descriptor: Sodium-driven chloride bicarbonate exchanger, CHOLESTEROL, CARBONATE ION, ... (5 entities in total)
• Functional Keywords: transmembrane, transport protein, membrane protein
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 2
• Total formula weight: 225287.93

Authors

Yang, S.,Capper, M.J.,Zilberg, G.,Warren, A.L.,Wacker, D. (deposition date: 2024-12-16, release date: 2026-08-05, Last modification date: 2026-09-09)

Primary citation

Yang, S.,Zhao, Y.,Vatansever, S.,Zilberg, G.,Capper, M.J.,Zhang, J.,Stamos, J.,Hutchinson, K.,Warren, A.L.,Stone, A.C.,Abbassi, A.,Purisic, E.,Ho, L.,Li, A.,Dai, J.,Schlessinger, A.,Zhang, B.,Wacker, D.
Structural insights enable drug discovery for the neuronal NBCn2 carbonate transporter.
Nat Commun, 17:-, 2026

PubMed Abstract: NBCn2 (SLC4A10), a member of the SLC4 solute carrier (SLC) family, is a sodium-dependent (bi)carbonate transporter that regulates acid extrusion in various brain regions. Mutations in NBCn2 cause severe neurodevelopmental disorders in humans, and knock out studies suggest that its role in regulating neuronal excitability could hold therapeutic potential for seizure disorders such as epilepsy. Despite its physiological importance, NBCn2's molecular mechanisms remain largely unknown, and there is limited availability of tool compounds to further probe its role in health and disease. Combining cryoEM with computational docking and simulation studies, we herein elucidate NBCn2's molecular architecture and substrate binding mechanisms on the atomic scale. Via structure-based drug discovery we further identify a compound series that inhibits NBCn2-mediated transport, and characterize its inhibitory mechanisms via cryoEM. Lastly, we showcase the potential of this compound series to template useful probes by demonstrating pharmacological activity both in primary culture as well as brain slices.

PubMed: 42637710
DOI: 10.1038/s41467-026-75444-4

Experimental method

ELECTRON MICROSCOPY (2.45 Å)