Authors
Okamoto, H., Oishi, A., Ikegami, K., McHugh, R., Masri, B., Kusakizako, T., Kobayashi, K., Karamitri, A., Cecon, E., Dam, J., Nagase, M., Tikhonova, I., Nureki, O., Jockers, R.
Abstract
G protein-coupled receptors (GPCRs) transduce extracellular stimuli into intracellular signals by coupling to various heterotrimeric G proteins. However, the rules governing G protein preference remain largely elusive. MT1 and MT2 are prototypical Gi/o-coupled GPCRs responding to melatonin, a hormone secreted in a circadian manner. We show here that MT1, but not MT2, couples also to Gs proteins in vitro and activates the Gs/cAMP pathway upon long-term melatonin exposure in vivo, mimicking physiological dawn conditions. We solved the cryo-electron microscopy structure of the melatonin-MT1-Gs complex at 3.0A resolution, which revealed a strikingly distinct binding mode compared to the MT1-Gi complex. The third intracellular loop of MT1 emerges as a key stabilizer for Gs coupling, a feature previously unrecognized. This is the first solved receptor-Gs complex of a primary Gi-coupled GPCRs, providing new structural and functional insights into G protein selectivity and circadian switch of G protein coupling.
Preprint server:
bioRxiv
The authors list and abstract were imported from bioRxiv on 09 Nov 2025.
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