Biophysical Dissection of Isolated GPCRs: The Adenosine A2A Receptor under the Bistouries
, Barbara Calamini 4,‡, Jérôme Castel 2,5, Laurent J. Catoire 6, Sarah Cianférani 2, Claire Demesmay 7, Gavin Ferguson 8, Gilles Ferry 9, Julie Kniazeff 1, Isabelle Krimm 10, Thierry Langer 11, Guillaume Lebon 8, Marie Ley 2, Miklos Nyerges 12, Magali Schwob 5,13, Catherine Venien-Bryan 14, Renaud Wagner 13, Gabrielle Zeder-Lutz 13 and add
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Round 1
Reviewer 1 Report
This is a fairly comprehensive overview of various methods used to determine adenosine A2A receptor structure and function. The description of the approaches used and their capabilities would be valuable for those studying other GPCRs. The last sections regarding specific A2A ligands are also useful, even though this info is specific for A2A receptor. This content of the review is excellent, but the text needs careful editing to improve grammar, style, and word usage. Just a few examples: line 50, “searchers” should be “researchers”; line 53, “in turns” should be “in turn”; line 59, rephrase “mastered environments”; line 95, “under a circular form” should be “in a cyclic form”; line 100, “as soon as 1974” should be “as early as 1974”. Editing is needed in many other places, in too many to point them all out.
Author Response
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Author Response File: 
Author Response.pdf
Reviewer 2 Report
The authors provide the most extensive review of biophysical dissection of isolated GPCRs on A2A receptor. The text flows very well and is logical organization.
I have some recommendations:
1. Tables listing each ligand (agonists and antagonists) and their molecular features, including functional motif, binding sites, EC50/IC50, pKi, pA2, and related references, are encouraged and might be helpful for readers to better understand these ligands.
2. Bioluminescence resonance energy transfer (BRET) and fluorescence resonance energy transfer (FRET)-based assays have been developed for different G-protein family pathways. This should be mentioned in this review.
3. AI technology, such as AlphaFold 1&2, is also a powerful tool to predict the 3D structure and protein-protein/ligand interaction. This technology might be applied to identify new ligands or new modulators of GPCRs.
4. Numerous studies have found that Ions, including Mg2+, Ca2+, Zn2+, Na+, could bind to multiple GPCRs, as endogenous modulators. These also can be added to this review
Author Response
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Author Response File: Author Response.pdf
