Step-wise activation of a Family C GPCR

Kumar, K. K.; Wang, H.; Habrian, C.; Latorraca, N. R.; Xu, J.; O'Brien, E. S.; Zhang, C.; Montabana, E.; Koehl, A.; Marqusee, S.; Isacoff, E. Y.; Kobilka, B. K.

doi:10.1101/2023.08.29.555158

bioRxiv · 10.1101/2023.08.29.555158

Step-wise activation of a Family C GPCR

Kumar, K. K.·Wang, H.·Habrian, C.·Latorraca, N. R.·Xu, J.·O'Brien, E. S.·Zhang, C.·Montabana, E.·Koehl, A.·Marqusee, S.·Isacoff, E. Y.·Kobilka, B. K.

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Abstract

Metabotropic glutamate receptors belong to a family of G protein-coupled receptors that are obligate dimers and possess a large extracellular ligand-binding domain (ECD) that is linked via a cysteine-rich domain (CRDs) to their 7-transmembrane (TM) domain. Upon activation, these receptors undergo a large conformational change to transmit the ligand binding signal from the ECD to the G protein-coupling TM. In this manuscript, we propose a model for a sequential, multistep activation mechanism of metabotropic glutamate receptor subtype 5. We present a series of structures in lipid nanodiscs, from inactive to fully active, including agonist-bound intermediate states. Further, using bulk and single-molecule fluorescence imaging we reveal distinct receptor conformations upon allosteric modulator and G protein binding.

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Kumar, K. K., Wang, H., Habrian, C., Latorraca, N. R., Xu, J., O'Brien, E. S., Zhang, C., Montabana, E., Koehl, A., Marqusee, S., Isacoff, E. Y., Kobilka, B. K.. 2023-08-30. Step-wise activation of a Family C GPCR. https://doi.org/10.1101/2023.08.29.555158

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