Key result
Mutation of Asp135 to alanine in the human 5-HT2B receptor abolished sarpogrelate binding and inositol phosphate accumulation, identifying Asp135 as a key residue for sarpogrelate interaction.
Asp135 in helix 3 of the human 5-HT2B receptor is critical for its interaction with sarpogrelate.
Supports targeted 5-HT2B ligand design; leaves open clinical translation in humans.
Based on radio-ligand binding and molecular modeling studies, sarpogrelate shows a moderate selectivity for 5-HT(2B) versus 5-HT(2A) receptors. To confirm the modeling data of sarpogrelate to 5-HT(2B) receptors predicting interaction of sarpogrelate towards Asp135 in helix 3 of 5-HT(2B) receptors, we constructed and characterized the mutation of this residue by site-directed mutagenesis. The Asp135Ala mutant did not exhibit any affinity for [(3)H]rauwolscine. Therefore, it was not possible to find sarpogrelate affinity to the mutant using [(3)H]rauwolscine. The mutation also abolished agonist-stimulated inositol phosphates formation. These results provide evidence that Asp135 is important for the interaction between 5-HT(2B) receptors and sarpogrelate.
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Muntasir et al. (2007) studied this question. Sarpogrelate vs. Wild-type 5-HT2B receptor was evaluated on Binding affinity (pKi) and functional affinity (pKb). Mutation of Asp135 to alanine in the human 5-HT2B receptor abolished sarpogrelate binding and inositol phosphate accumulation, identifying Asp135 as a key residue for sarpogrelate interaction.
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