An inverse agonist of orphan receptor GPR61 reveals a novel allosteric mechanism

Lees, J. A.; Dias, J. M.; Rajamohan, F.; Fortin, J.-P.; O'Connor, R.; Kong, J. X.; Hughes, E.; Fisher, E. L.; Tuttle, J. B.; Lovett, G.; Kormos, B. L.; Unwalla, R. J.; Zhang, L.; Dechert Schmidt, A.-M.; Zhou, D.; Stevens, K. A.; Fennell, K. F.; Varghese, A. H.; Maxwell, A.; Cote, E. E.; Zhang, Y.; Han, S.

doi:10.1101/2023.05.01.538732

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bioRxiv · 10.1101/2023.05.01.538732

An inverse agonist of orphan receptor GPR61 reveals a novel allosteric mechanism

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Abstract

GPR61 is a biogenic amine receptor-related orphan GPCR associated with phenotypes relating to appetite and thus, is of interest as a druggable target to treat disorders of metabolism and body weight, such as obesity and cachexia. To date, lack of structural information or a known biological ligand or tool compound has hindered comprehensive efforts to study its structure and function. Here, we report the first ever structural characterization of GPR61, in both its active-like complex with heterotrimeric G protein and in its inactive state. Moreover, we report the discovery of a potent and selective small-molecule inverse agonist against GPR61 and structural elucidation of its unprecedented allosteric site and mode of action. These findings offer key mechanistic insights into an orphan GPCR, while providing both a new structural framework and tool compound to support further studies of GPR61 function and modulation.

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Lees, J. A., Dias, J. M., Rajamohan, F., Fortin, J.-P., O'Connor, R., Kong, J. X., Hughes, E., Fisher, E. L., Tuttle, J. B., Lovett, G., Kormos, B. L., Unwalla, R. J., Zhang, L., Dechert Schmidt, A.-M., Zhou, D., Stevens, K. A., Fennell, K. F., Varghese, A. H., Maxwell, A., Cote, E. E., Zhang, Y., Han, S.. 2023-05-01. An inverse agonist of orphan receptor GPR61 reveals a novel allosteric mechanism. https://doi.org/10.1101/2023.05.01.538732

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