Related Experiment Video

Updated: Nov 20, 2025

Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications
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Drug-induced Sensitization of Adenylyl Cyclase: Assay Streamlining and Miniaturization for Small Molecule and siRNA Screening Applications

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Gαi1 inhibition mechanism of ATP-bound adenylyl cyclase type 5

Daniele Narzi1, Siri C van Keulen1, Ursula Röthlisberger1

  • 1Institut des Sciences et Ingénierie Chimiques, École Polytechnicque Fédérale de Lausanne (EPFL), Lausanne, Switzerland.

Plos One
|January 25, 2021
PubMed

Insights

The inhibitory Gαi subunit prevents adenylyl cyclase (AC) activity by blocking a reactive ATP conformation. This molecular dynamics study clarifies the inhibition mechanism of AC5:Gαi interactions.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Structural Biology

Background:

  • Cyclic adenosine monophosphate (cAMP) is a crucial second messenger in eukaryotic signaling pathways.
  • Adenylyl cyclase (AC) enzymes catalyze the conversion of adenosine triphosphate (ATP) to cAMP.
  • AC activity is regulated by stimulatory (Gαs) and inhibitory (Gαi) G protein subunits, but the Gαi inhibition mechanism remains unclear.

Purpose of the Study:

  • To investigate the molecular basis of adenylyl cyclase type 5 (AC5) inhibition by the Gαi subunit.
  • To understand the conformational changes in ATP-bound AC5 upon Gαi association.

Main Methods:

  • Classical molecular dynamics simulations were employed.
  • Simulations were performed on isolated holo AC5 and the holo binary complex AC5:Gαi.

Main Results:

  • Gαi association induces conformational changes in ATP-bound AC5.
  • The inhibitory effect of Gαi is mediated by preventing the formation of a catalytically reactive ATP conformation.

Conclusions:

  • Gαi inhibits AC5 by altering its conformation to disfavor ATP activation.
  • This study provides molecular insights into the mechanism of AC inhibition by Gαi subunits.

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