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.
Show 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.
Matching journals
The top 2 journals account for 50% of the predicted probability mass.