Gαi1 inhibition mechanism of ATP-bound adenylyl cyclase type 5.

Daniele Narzi, Siri C van Keulen, Ursula Röthlisberger

PloS one 2021

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Conversion of adenosine triphosphate (ATP) to the second messenger cyclic adenosine monophosphate (cAMP) is an essential reaction mechanism that takes place in eukaryotes, triggering a variety of signal transduction pathways. ATP conversion is catalyzed by the enzyme adenylyl cyclase (AC), which can be regulated by binding inhibitory, Gαi, and stimulatory, Gαs subunits. In the past twenty years, several crystal structures of AC in isolated form and complexed to Gαs subunits have been resolved. Nevertheless, the molecular basis of the inhibition mechanism of AC, induced by Gαi, is still far from being fully understood. Here, classical molecular dynamics simulations of the isolated holo AC protein type 5 and the holo binary complex AC5:Gαi have been analyzed to investigate the conformational impact of Gαi association on ATP-bound AC5. The results show that Gαi appears to inhibit the activity of AC5 by preventing the formation of a reactive ATP conformation.

Citation

Daniele Narzi, Siri C van Keulen, Ursula Röthlisberger. Gαi1 inhibition mechanism of ATP-bound adenylyl cyclase type 5. PloS one. 2021;16(1):e0245197