Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation

Recent crystal structures of G-protein-coupled receptors (GPCRs) have revealed ordered internal water molecules, raising questions about the functional role of those waters for receptor activation that could not be answered by the static structures. Here, we used molecular dynamics simulations to monitor-at atomic and high temporal resolutionconformational changes of central importance for the activation of three prototypical GPCRs with known crystal structures: the adenosine A 2A receptor, the b 2 -adrenergic receptor and rhodopsin. Our simulations reveal that a hydrophobic layer of amino acid residues next to the characteristic NPxxY motif forms a gate that opens to form a continuous water channel only upon receptor activation. The highly conserved tyrosine residue Y 7.53 undergoes transitions between three distinct conformations representative of inactive, G-protein activated and GPCR metastates. Additional analysis of the available GPCR crystal structures reveals general principles governing the functional roles of internal waters in GPCRs.

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“…2b). The HL2 was also observed within two independent additional 1.6 ms MD simulations, starting from the NECA/ A 2A R II structure 13 (Fig. 2c).…”

Section: Resultsmentioning

confidence: 85%

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

et al. 2014

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“…Complexes of thermostabilized A 2A AR with the natural agonist adenosine (RCSB ID: 2YDO) and the synthetic agonist NECA (RCSB ID: 2YDV) were recently solved [3]. These new structures represent intermediate conformations between inactive and active states of the receptor, and are very similar to the agonist complex reported by Xu and colleagues [4], suggesting a common behaviour in the activation of all GPCRs.…”

Section: Commentarymentioning

confidence: 55%

Class A GPCRs: a multifaceted reality

Parravicini

Sensi

Eberini

2011

Purinergic Signalling

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“…During activation, agonist binding generally induces a 2 Å shift of TM3 towards the extracellular side of the receptor. This movement alters the position of the highly conserved DRY motif of TM3 which, after activation, interacts with the heterotrimeric G protein subunit on the cytosolic side of the receptor [39,40]. It is predicted that ligand binding provokes this movement of TM3 and it is likely that any mutations which alter its interactions are likely to affect activity.…”

Section: Discussionmentioning

confidence: 99%

Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin‐1 receptor in the grey squirrel (Sciurus carolinensis)

et al. 2014

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a b s t r a c tThe melanocortin-1 receptor (MC1R) is a key regulator of mammalian pigmentation. Melanism in the grey squirrel is associated with an eight amino acid deletion in the mutant melanocortin-1 receptor with 24 base pair deletion (MC1RD24) variant. We demonstrate that the MC1RD24 exhibits a higher basal activity than the wildtype MC1R (MC1R-wt). We demonstrate that agouti signalling protein (ASIP) is an inverse agonist to the MC1R-wt but is an agonist to the MC1RD24. We conclude that the deletion in the MC1RD24 leads to a receptor with a high basal activity which is further activated by ASIP. This is the first report of ASIP acting as an agonist to MC1R.

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Agonist-bound adenosine A2A receptor structures reveal common features of GPCR activation

Cited by 820 publications

References 44 publications

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Activation of G-protein-coupled receptors correlates with the formation of a continuous internal water pathway

Class A GPCRs: a multifaceted reality

Agouti signalling protein is an inverse agonist to the wildtype and agonist to the melanic variant of the melanocortin‐1 receptor in the grey squirrel (Sciurus carolinensis)

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