Unknown

Dataset Information

0

Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions.


ABSTRACT: The activation process of G protein-coupled receptors (GPCRs) has been extensively studied, both experimentally and computationally. In particular, Molecular Dynamics (MD) simulations have proven useful in exploring GPCR conformational space. The typical behaviour of class A GPCRs, when subjected to unbiased MD simulations from their crystallized inactive state, is to fluctuate between inactive and intermediate(s) conformations, even with bound agonist. Fully active conformation(s) are rarely stabilized unless a G protein is also bound. Despite several crystal structures of the adenosine A2a receptor (A2aR) having been resolved in complex with co-crystallized agonists and Gs protein, its agonist-mediated activation process is still not completely understood. In order to thoroughly examine the conformational landscape of A2aR activation, we performed unbiased microsecond-length MD simulations in quadruplicate, starting from the inactive conformation either in apo or with bound agonists: endogenous adenosine or synthetic NECA, embedded in two homogeneous phospholipid membranes: 1,2-dioleoyl-sn-glycerol-3-phosphoglycerol (DOPG) or 1,2-dioleoyl-sn-glycerol-3-phosphocholine (DOPC). In DOPC with bound adenosine or NECA, we observe transition to an intermediate receptor conformation consistent with the known adenosine-bound crystal state. In apo state in DOPG, two different intermediate conformations are obtained. One is similar to that observed with bound adenosine in DOPC, while the other is closer to the active state but not yet fully active. Exclusively, in DOPG with bound adenosine or NECA, we reproducibly identify receptor conformations with fully active features, which are able to dock Gs protein. These different receptor conformations can be attributed to the action/absence of agonist and phospholipid-mediated allosteric effects on the intracellular side of the receptor.

SUBMITTER: Bruzzese A 

PROVIDER: S-EPMC7188303 | biostudies-literature | 2020 Apr

REPOSITORIES: biostudies-literature

altmetric image

Publications

Insights into adenosine A2A receptor activation through cooperative modulation of agonist and allosteric lipid interactions.

Bruzzese Agustín A   Dalton James A R JAR   Giraldo Jesús J  

PLoS computational biology 20200416 4


The activation process of G protein-coupled receptors (GPCRs) has been extensively studied, both experimentally and computationally. In particular, Molecular Dynamics (MD) simulations have proven useful in exploring GPCR conformational space. The typical behaviour of class A GPCRs, when subjected to unbiased MD simulations from their crystallized inactive state, is to fluctuate between inactive and intermediate(s) conformations, even with bound agonist. Fully active conformation(s) are rarely st  ...[more]

Similar Datasets

| S-EPMC8730723 | biostudies-literature
| S-EPMC8880556 | biostudies-literature
| S-EPMC8581623 | biostudies-literature
| S-EPMC3146096 | biostudies-literature
| S-EPMC5034350 | biostudies-literature
| S-EPMC3086811 | biostudies-literature
| S-EPMC6445292 | biostudies-literature
| S-EPMC2721769 | biostudies-literature
| S-EPMC6141747 | biostudies-literature
| S-EPMC8921400 | biostudies-literature