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

• Published in: Biomolecules (Basel, Switzerland) Vol. 10; no. 9; p. 1330
• Main Authors: Frezza, Elisa, Amans, Tina-Méryl, Martin, Juliette
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.09.2020; MDPI
• Subjects: Adenosine Triphosphate - chemistry; Adenosine Triphosphate - metabolism; Adenylyl Cyclases - chemistry; Adenylyl Cyclases - metabolism; Allosteric Regulation; allostery; Animals; Biochemistry, Molecular Biology; Bioinformatics; Cellular signal transduction; Computer Science; docking; enzyme activity; flexibility; G proteins; GTP-Binding Protein alpha Subunits, Gi-Go - chemistry; GTP-Binding Protein alpha Subunits, Gi-Go - metabolism; Health aspects; Kinetics; Life Sciences; Mice; molecular dynamics; Molecular Dynamics Simulation; Protein Binding; Protein Domains; protein-protein interactions; Structural Biology; France; docking; flexibility; enzyme activity; homology models; molecular dynamics; allostery; protein-protein interactions
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom10091330

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.