The Toggle Switch

Toward the intracellular side just below the covalently bound retinal in the rhodopsin X-ray structures, a conserved tryptophan (W6.48, using established nomenclature [45], see Fig. 16.1c) is part of a series of residues, in addition to a network of conserved water molecules, that help to propagate the activation/ inactivation signal by interacting near the intracellular side along the inner transmembrane region. Believed to control this signal through a change of its rotational state, W6.48 is known as the "toggle switch" [46]. In rhodopsin, the

P-ionone ring of retinal, which occupies a deep region of the binding pocket, interacts directly with W6.48, which is thereby locked into its inactive rotamer. The same inactivating conformation is achieved in the high-resolution p2AR X-ray structure, even though the binding of carazolol does not interact directly with W6.48 due to the ligand 's relatively shallow occupancy of the binding cavity. Carazolol, instead, interacts with Phe290 (corresponding to an alanine residue in rhodopsin), which forces W6.48 to adopt the same postulated inactivating conformation as in rhodopsin. Although the ligand of the A2a adeno-sine X-ray structure is even further from W6.48, the protein is still found in the inactive state, where His250 plays the role of Phe290 in the p2AR structure.

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