Abstract
Adenylyl cyclases (ACs) catalyze the biosynthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) and play an important role in many signal transduction pathways. The enzymatic activity of ACs is carefully controlled by a variety of molecules, including G-protein subunits that can both stimulate and inhibit cAMP production. Using homology models developed from existing structural data, we have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 isoform of adenylyl cyclase and on its complexes with ATP and with the stimulatory G-protein subunit Gsα. The results show that both ATP and Gsα binding have significant effects on the structure and flexibility of adenylyl cyclase. New data on ATP bound to AC5 in the absence of Gsα notably help to explain how Gsα binding enhances enzyme activity and could aid product release. Simulations also suggest a possible coupling between ATP binding and interactions with the inhibitory G-protein subunit Gαi.
Highlights
Cyclic adenosine monophosphate is a universal second messenger in signal transduction based on G-protein coupled receptors (GPCR) in eukaryotes [1]
In the absence of any structural information on a single non-chimeric isoform of adenylyl cyclase, or on the catalytic domains of the enzyme without the stimulating G-protein subunit Gsα, we use a combination of homology modeling and molecular dynamics to try to understand how protein or ligand binding can modify the conformation or the dynamics of AC5 and subsequently impact on its enzymatic function
We have studied the behavior of four molecular species: isolated AC5, AC5 with adenosine triphosphate (ATP) and two Mg2+ ions in its active site (AC5+ATP), AC5 bound to the activating G-protein subunit Gsα (AC5+Gsα+GTP) and AC5 bound to both ATP and Gsα (AC5+ATP+Gsα+GTP)
Summary
Cyclic adenosine monophosphate (cAMP) is a universal second messenger in signal transduction based on G-protein coupled receptors (GPCR) in eukaryotes [1]. It is responsible for amplifying stimuli received by the cell [2,3,4,5,6]. It is not surprising that cAMP levels must be tightly controlled and the enzymes responsible for cAMP synthesis are highly regulated [9] This family of enzymes, the adenylyl cyclases ( commonly known as adenylate cyclases), has nine members (hereafter termed AC1-9). The latter is divided into two pseudosymmetric domains, termed C1 and C2, each containing approximately 230 amino acid residues and sharing roughly 40% sequence
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