#ALLOSTERIC ACTIVATOR ACTIVATOR#

The structure reveals that the compounds are selective for sAC because they bind to the sAC-specific, allosteric binding site for the physiological activator bicarbonate. To analyze the interaction details, we solved a crystal structure of an sAC Inhibition appears mostly non-competitive with the substrate ATP, indicating that they act via an allosteric site. Here we identify the bisphenols bithionol and hexachlorophene as potent, sAC-specific inhibitors. for diabetes, glaucoma, and a male contraceptive. Via bicarbonate regulation, sAC acts as a physiological sensor for pH/bicarbonate/CO2, and it has been implicated as a therapeutic target, e.g. Transmembrane ACs respond to G proteins, whereas sAC is uniquely activated by bicarbonate.

Despite similarities in their catalytic domains, these ACs differ in regulation. In mammals, cAMP is synthesized by nine transmembrane adenylyl cyclases (ACs) and one soluble AC (sAC). The signaling molecule cAMP regulates functions ranging from bacterial transcription to mammalian memory. Bithionol Potently Inhibits Human Soluble Adenylyl Cyclase through Binding to the Allosteric Activator Site.

Allosteric activator