Allosteric Inhibition of Adenylyl Cyclase Type 5 by G-Protein: A Molecular Dynamics Study

Biomolecules. 2020 Sep 17;10(9):1330. doi: 10.3390/biom10091330.

Abstract

Adenylyl cyclases (ACs) have a crucial role in many signal transduction pathways, in particular in the intricate control of cyclic AMP (cAMP) generation from adenosine triphosphate (ATP). Using homology models developed from existing structural data and docking experiments, we have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 isoform of adenylyl cyclase bound to the inhibitory G-protein subunit Gαi in the presence and in the absence of ATP. The results show that Gαi has significant effects on the structure and flexibility of adenylyl cyclase, as observed earlier for the binding of ATP and Gsα. New data on Gαi bound to the C1 domain of AC5 help explain how Gαi inhibits enzyme activity and obtain insight on its regulation. Simulations also suggest a crucial role of ATP in the regulation of the stimulation and inhibition of AC5.

Keywords: allostery; docking; enzyme activity; flexibility; homology models; molecular dynamics; protein-protein interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / chemistry
  • Adenosine Triphosphate / metabolism
  • Adenylyl Cyclases / chemistry*
  • Adenylyl Cyclases / metabolism
  • Allosteric Regulation
  • Animals
  • GTP-Binding Protein alpha Subunits, Gi-Go / chemistry*
  • GTP-Binding Protein alpha Subunits, Gi-Go / metabolism
  • Kinetics
  • Mice
  • Molecular Dynamics Simulation*
  • Protein Binding
  • Protein Domains*

Substances

  • Adenosine Triphosphate
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Adenylyl Cyclases
  • adenylyl cyclase type V