The pocketome of G-protein-coupled receptors reveals previously untargeted allosteric sites

Janik B. Hedderich, Margherita Persechino, Katharina Becker, Franziska M. Heydenreich, Torben Gutermuth, Michel Bouvier, Moritz Bünemann and Peter Kolb ()
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Janik B. Hedderich: Philipps-University Marburg
Margherita Persechino: Philipps-University Marburg
Katharina Becker: Philipps-University Marburg
Franziska M. Heydenreich: Stanford University School of Medicine
Torben Gutermuth: Philipps-University Marburg
Michel Bouvier: Université de Montréal
Moritz Bünemann: Philipps-University Marburg
Peter Kolb: Philipps-University Marburg

Nature Communications, 2022, vol. 13, issue 1, 1-12

Abstract: Abstract G-protein-coupled receptors do not only feature the orthosteric pockets, where most endogenous agonists bind, but also a multitude of other allosteric pockets that have come into the focus as potential binding sites for synthetic modulators. Here, to better characterise such pockets, we investigate 557 GPCR structures by exhaustively docking small molecular probes in silico and converting the ensemble of binding locations to pocket-defining volumes. Our analysis confirms all previously identified pockets and reveals nine previously untargeted sites. In order to test for the feasibility of functional modulation of receptors through binding of a ligand to such sites, we mutate residues in two sites, in two model receptors, the muscarinic acetylcholine receptor M3 and β2-adrenergic receptor. Moreover, we analyse the correlation of inter-residue contacts with the activation states of receptors and show that contact patterns closely correlating with activation indeed coincide with these sites.

Date: 2022
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DOI: 10.1038/s41467-022-29609-6

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