Gαi1 inhibition mechanism of ATP-bound adenylyl cyclase type 5

• Published in: PloS one 2021-01, Vol.16 (1), p.e0245197-e0245197
• Main Authors: Narzi, Daniele, van Keulen, Siri C, Röthlisberger, Ursula
• Format: Article
• Language: English
• Subjects: Adenosine monophosphate; Adenosine triphosphate; Adenylate cyclase; Adenylyl Cyclases - chemistry; ATP; Binding sites; Biology and Life Sciences; Computer applications; Cyclic AMP; Cyclic AMP - chemistry; Enzymes; G protein-coupled receptors; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry; Humans; Kinases; Membranes; Metabolism; Molecular Dynamics Simulation; Multiprotein Complexes - chemistry; Nucleotides; Physical Sciences; Protein Structure, Quaternary; Proteins; Reinforcement; Signal transduction; Simulation; Substrates
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0245197

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.