Structure (London), 2019-04, Vol.27 (4), p.703
2019
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Details
- Autor(en) / Beteiligte
- Titel
- Dynamic Role of the G Protein in Stabilizing the Active State of the Adenosine A 2A Receptor
- Ist Teil von
- Structure (London), 2019-04, Vol.27 (4), p.703
- Ort / Verlag
- United States
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Agonist binding in the extracellular region of the G protein-coupled adenosine A2A receptor increases its affinity to the G proteins in the intracellular region, and vice versa. The structural basis for this effect is not evident from the crystal structures of A R in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A receptor, we observed that the agonists show decreased ligand mobility, lower entropy of the extracellular loops in the active-intermediate state compared with the inactive state. In contrast, the entropy of the intracellular region increases to prime the receptor for coupling the G protein. Coupling of the G protein to A R shrinks the agonist binding site, making tighter receptor agonist contacts with an increase in the strength of allosteric communication compared with the active-intermediate state. These insights provide a strong basis for structure-based ligand design studies.
- Sprache
- Englisch
- Identifikatoren
- eISSN: 1878-4186DOI: 10.1016/j.str.2018.12.007Titel-ID: cdi_pubmed_primary_30713025
- Format
- –
- Schlagworte
- Adenosine - chemistry, Adenosine - metabolism, Adenosine A2 Receptor Agonists - chemistry, Adenosine A2 Receptor Agonists - metabolism, Adenosine-5'-(N-ethylcarboxamide) - chemistry, Adenosine-5'-(N-ethylcarboxamide) - metabolism, Allosteric Regulation, Allosteric Site, Catalytic Domain, GTP-Binding Proteins - chemistry, GTP-Binding Proteins - genetics, GTP-Binding Proteins - metabolism, Humans, Ligands, Models, Molecular, Molecular Dynamics Simulation, Protein Binding, Protein Conformation, alpha-Helical, Protein Conformation, beta-Strand, Protein Interaction Domains and Motifs, Protein Stability, Receptor, Adenosine A2A - chemistry, Receptor, Adenosine A2A - genetics, Receptor, Adenosine A2A - metabolism, Thermodynamics