A(3) Adenosine Receptor Activation Mechanisms: Molecular Dynamics Analysis of Inactive, Active, and Fully Active States
| Autor: | Priscila Rubio, Antonella Ciancetta, David I. Lieberman, Kenneth A. Jacobson |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Protein Conformation
Gi alpha subunit Activation Molecular Dynamics Simulation 01 natural sciences Article NO Activation Adenosine receptor G protein-coupled receptor Homology modeling Molecular dynamics simulation Purinergic signaling Molecular dynamics 0103 physical sciences Drug Discovery Molecule Humans Homology modeling G protein-coupled receptor Physical and Theoretical Chemistry Receptor 010304 chemical physics Chemistry Purinergic signaling Receptor Adenosine A3 Adenosine receptor Purinergic signalling 0104 chemical sciences Computer Science Applications 010404 medicinal & biomolecular chemistry Mutation Biophysics Mutagenesis Site-Directed |
| Zdroj: | J Comput Aided Mol Des |
| Popis: | We investigated the Gi-coupled A(3) adenosine receptor (A(3)AR) activation mechanism by running 7.2 μs of molecular dynamics (MD) simulations. Based on homology to G protein-coupled receptor (GPCR) structures, three constitutively active mutant (CAM) and the wild-type (WT) A(3)ARs in the apo form were modeled. Conformational signatures associated with three different receptor states (inactive R, active R*, and bound to Gi protein mimic) were predicted by analyzing and comparing the CAMs with WT receptor and by considering site-directed mutagenesis data. Detected signatures that were correlated with receptor state included: Persistent salt-bridges involving key charged residues for activation (including a novel, putative ionic lock), rotameric state of conserved W(6.48), and Na(+) ions and water molecules present. Active-coupled state signatures similar to the X-ray structures of β(2) adrenergic receptor-Gs protein and A(2A)AR-mini-Gs and the recently solved cryo-EM A(1)AR-Gi complexes were found. Our MD analysis suggests that constitutive activation might arise from the D107(3.49)-R108(3.50) ionic lock destabilization in R and the D107(3.49)-R111(3.53) ionic lock stabilization in R* that presumably lowers the energy barrier associated with an R to R* transition. This study provides new opportunities to understand the underlying interactions of different receptor states of other Gi protein-coupled GPCRs. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|