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The intracellular portion of TM6 swings out to create a pocket for the docking of G protein (or beta arrestin). This conformational change results from counterclockwise rotation (looking from the extracellular side) of TM6 generated by the Transmission Switch (see below). The inactive state is stabilized by the Na Pocket (see below) and the Hydrophobic Lock (see below). During receptor activation, the Na Pocket collapses and the Hydrophobic Lock is broken.
Layer 1 at the bottom of the ligand binding pocket:
Transmission Switch (TM6 Rotation): TM3-5-6 Contraction
This switch is all about TM6 rotation
F6.44 - W6.48 interaction ↓ in activation
I3.40 - W6.48 interaction ↑ in activation
5.51 - F6.44 interaction ↑ in activation
Na+ Pocket (inactivating Na binding site):
Collapse in activation
D2.50, S3.39, N7.49
L3.43 - N7.49 interaction ↑ in activation (connection between Layer 1 and Layer 2)
Layer 2
Hydrophobic Lock (inactivating lock):
L3.43, 6.40, 6.41
Breaking of the lock leads to TM3 - TM6 separation
5.55 - 6.41 interaction ↑ in activation
Y5.58 - 6.40 interaction ↑ in activation
Layer 3
TM3 - 7 contraction
Y7.53 - 1.53/8.50 ↓ in activation
Y7.53 - 3.43/3.46/3.50 ↑ in activation
Layer 4
TM3 - TM6 Separation
The transmission switch (I3.40-W6.48, 5.51-F6.44) causes rotation of TM6.
Loosening of the hydrophobic lock (L3.43, 6.40, 6.41) allows separation of TM3 and TM6.
The collapse of the Na pocket allows tighter association between TM3 and TM7.
A recent NMR study on A2AR (Eddy et al., 2018) demonstrated the strong coupling between allosteric switch D2.50 and toggle switch W6.48.
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