Abstract
SummaryAgonist 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 A2AR in various conformational states since it stems from the receptor dynamics. Using atomistic molecular dynamics simulations on four different conformational states of the adenosine A2A 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 A2AR 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.
Highlights
The adenosine A2A receptor (A2AR) is a G protein-coupled receptor (GPCR) that is activated in vivo by the agonist adenosine (Fredholm et al, 2011)
Atomistic molecular dynamics (MD) simulations were performed on A2AR bound to the agonists adenosine (ADO) or 5-N-ethylcarboxamidoadenosine (NECA), each in four different conformational states: (1) the inactive state of the receptor, R; (2) the active-intermediate state, R0; (3) the mini-Gs bound fully active state, R*$G; and (4) a metastable state, R*$GÀ, formed in silico by removal of mini-Gs from R*$G
The inactive state with NECA bound was generated from the crystal structure of A2AR bound to the inverse agonist ZM241385 (Dore et al, 2011) by replacement of the ligand with NECA followed by an equilibration protocol and MD production runs
Summary
The adenosine A2A receptor (A2AR) is a G protein-coupled receptor (GPCR) that is activated in vivo by the agonist adenosine (Fredholm et al, 2011). The mechanism of activation conforms to the canonical paradigm (Rasmussen et al, 2011a) where agonist binding results in a slight contraction of the orthosteric binding pocket, rotamer changes of the hydrophobic gating residues Pro5.50-Ile3.40-Phe6.44 and opening of a cleft on the cytoplasmic face of the receptor primarily through an outward movement of transmembrane helix 6 (TM6). The C-terminal helix of Gs, known as the a5 helix, binds in this cleft, resulting in nucleotide exchange and activation of the G protein (Carpenter et al, 2016; Rasmussen et al, 2011b)
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