Crystal structures of human soluble adenylyl cyclase reveal mechanisms of catalysis and of its activation through bicarbonate
Abstract
Soluble adenylyl cyclase (sAC) generates the ubiquitous signaling molecule cAMP in response to bicarbonate. In physiological systems, bicarbonate is in nearly instantaneous equilibrium with carbon dioxide and pH; therefore, sAC, and its evolutionarily related cyclases, serve as nature's carbon dioxide/bicarbonate/pH sensors. In particular, bicarbonate regulation of mammalian sAC mediates numerous cellular processes, from sperm activation to pH homeostasis and mitochondrial ATP synthesis. We solved crystal structures of sAC's catalytic domains in complex with substrate, products, and regulators. The structures reveal insights into sAC catalysis, how bicarbonate binds to and activates sAC, and how sAC can be inhibited by a drug. Our results reveal mechanisms that will facilitate the development of drugs targeting this signaling system.
- Publication:
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Proceedings of the National Academy of Science
- Pub Date:
- March 2014
- DOI:
- 10.1073/pnas.1322778111
- Bibcode:
- 2014PNAS..111.3727K