Crystal Structure of Carbonic Anhydrase II in Complex with an Activating Ligand: Implications in Neuronal Function

Carbonic anhydrase (CA) plays a key role in neuronal signaling, providing bicarbonate and proton ions for GABAergic and glutamatergic neuronal function. Activation of CA isoforms expressed in neurons have been shown to have implications in the prognosis of Alzheimer’s disease and dementia, while inhibitors of CAs are clinically used in the treatment of epilepsy, emphasizing the importance of this family of enzymes in both disease and normal neuronal function. Previously, compounds have been reported to enhance activity of CAs in an aging rat model, but their mechanism of action was not known. We report the 1.6 Å resolution structure of an imidazole-based CA activator in complex with the ubiquitously-expressed human CA II. Based on the structure, a proposed mechanism of CA activation by the compound and its potential applications in the neurobiology of aging are discussed.