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Pré-Publication, Document De Travail Année : 2020

Allosteric inhibition of adenylyl cyclase type 5 by G-protein: a molecular dynamics study

Elisa Frezza
Tina-Méryl Amans
  • Fonction : Auteur
Juliette Martin

Résumé

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 have 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 to explain how Gαi inhibits enzyme activity and to get insight on its regulation. Simulations also suggest a crucial role of ATP in the regulation of stimulation and inhibition of AC5.
11 12 Adenylyl cyclases (ACs) have a crucial role in many signal transduction pathways, in particular 13 in the intricate control of cyclic AMP (cAMP) generation from adenosine triphosphate (ATP). 14 Using homology models developed from existing structural data and docking experiments, we 15 have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 16 isoform of adenylyl cyclase bound to the inhibitory G-protein subunit Gαi in the presence and in 17 the absence of ATP. The results show that Gαi have significant effects on the structure and 18 flexibility of adenylyl cyclase, as observed earlier for the binding of ATP and Gsα. New data on 19 Gαi bound to the C1 domain of AC5 help to explain how Gαi inhibits enzyme activity and to get 20 insight on its regulation. Simulations also suggest a crucial role of ATP in the regulation of 21 stimulation and inhibition of AC5.
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hal-02988423 , version 1 (05-11-2020)

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Elisa Frezza, Tina-Méryl Amans, Juliette Martin. Allosteric inhibition of adenylyl cyclase type 5 by G-protein: a molecular dynamics study. 2020. ⟨hal-02988423⟩

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