Mapping the binding site pocket of the serotonin 5-Hydroxytryptamine2A receptor. Ser3.36(159) provides a second interaction site for the protonated amine of serotonin but not of lysergic acid diethylamide or bufotenin.
The Journal of biological chemistry June 21, 1996 N Almaula, B J Ebersole, D Zhang et al. 147 citations
The neurotransmitter serotonin (5-HT) activates the 5-HT2A receptor by binding through its amine group to a specific aspartate residue. Computer simulations suggested that serotonin also forms a hydrogen bond with a nearby serine residue, but other ligands like LSD and N,N-dimethyl serotonin cannot form this bond due to steric hindrance. Mutating the serine to alanine reduced serotonin affinity 18-fold, and to cysteine reduced it 5-fold, while LSD affinity was unaffected. N,N-dimethyl serotonin showed a small 3-fold decrease only with alanine mutation. These results identify a binding mode where two receptor side chains interact with the same functional group of certain ligands, orienting them in the binding pocket and potentially affecting receptor activation.