Structural insights and drug discovery at a brain carbonate transporter

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. In the choroid plexus, NBCn2 has been shown to regulate cerebrospinal fluid seretion across the epithelium, 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 no useful tool compounds are available to further probe its role in health and disease. Combining cryo-EM 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 uncover a compound series that inhibits NBCn2-mediated transport, and characterize its inhibitory mechanisms via cryo-EM. Lastly, we showcase the potential of this compound series to template useful probes by demonstrating pharmacological activity both in primary culture as well as a brain slices.