MMSB, Univ. Lyon I / CNRS UMR 5086, Institut de Biologie et Chimie des Protéines, Lyon, France.
PLoS One. 2018 Apr 25;13(4):e0196207. doi: 10.1371/journal.pone.0196207. eCollection 2018.
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.
腺苷酸环化酶（ACs）催化三磷酸腺苷（ATP）生成环腺苷酸（cAMP），在许多信号转导途径中发挥重要作用。ACs 的酶活性受到多种分子的精细调控，包括可以刺激和抑制 cAMP 产生的 G 蛋白亚基。我们利用现有结构数据开发的同源模型，对腺苷酸环化酶 AC5 同工型及其与 ATP 和刺激 G 蛋白亚基 Gsα 的复合物进行了全原子、微秒级别的分子动力学模拟。结果表明，ATP 和 Gsα 的结合对腺苷酸环化酶的结构和灵活性都有显著影响。与 Gsα 结合增强酶活性的机制，以及与抑制性 G 蛋白亚基 Gαi 的相互作用可能存在耦合。没有 Gsα 结合的情况下，ATP 结合的新数据特别有助于解释 Gsα 结合如何增强酶活性并有助于产物释放。模拟还表明，ATP 结合与与抑制性 G 蛋白亚基 Gαi 的相互作用之间可能存在偶联。
