Exploring the inhibition mechanism of adenylyl cyclase type 5 by n-terminal myristoylated Gα(i1)

Adenylyl cyclase (AC) is an important messenger involved in G-protein-coupled-receptor signal transduction pathways, which is a well-known target for drug development. AC is regulated by activated stimulatory (Gα(s)) and inhibitory (Gα(i)) G proteins in the cytosol. Although experimental studies have shown that these Gα subunits can stimulate or inhibit AC’s function in a non-competitive way, it is not well understood what the difference is in their mode of action as both Gα subunits appear structurally very similar in a non-lipidated state. However, a significant difference between Gα(s) and Gα(i) is that while Gα(s) does not require any lipidation in order to stimulate AC, N-terminal myristoylation is crucial for Gα(i)’s inhibitory function as AC is not inhibited by non-myristoylated Gα(i). At present, only the conformation of the complex including Gα(s) and AC has been resolved via X-ray crystallography. Therefore, understanding the interaction between Gα(i) and AC is important as it will provide more insight into the unknown mechanism of AC regulation. This study demonstrates via classical molecular dynamics simulations that the myristoylated Gα(i1) structure is able to interact with apo adenylyl cyclase type 5 in a way that causes inhibition of the catalytic function of the enzyme, suggesting that Gα lipidation could play a crucial role in AC regulation and in regulating G protein function by affecting Gα(i)’s active conformation.