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Furthermore, a cluster of conserved hydrophobic residues, located between the central hydrogen bond network and the TM2–TM3–TM6–TM7 network, helps in stabilizing the P 6.47 XXG 6.50 motif (TM6) in the inactive conformation ( 2.46 , R348 6.37 , N406 7.61 , E408 8.49 ), including the destabilization of the P 6.47 XXG 6.50 motif, which facilitates the movement of TM6, leading to the binding of the G protein and activation of the GLP-1R (Figure 17)

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Orforglipron’s oral format aligns with broader regulatory interest in improving treatment accessibility and adherence, particularly in chronic metabolic conditions