Role of threonine 342 in helix 7 of the 5-hydroxytryptamine type 1D receptor in ligand binding: An indirect mechanism for receptor selectivity

Recent mutations of the 5-hydroxytryptamine (5-HT)_1B and 5-HT_1D receptor subtypes suggest that a threonine in the seventh transmembrane helix may be responsible for the selectivity of these receptors. A molecular dynamics simulation of a three-dimensional model of the 5-HT_1D receptor interacting with a selective agonist, sumatriptan, shows that, although Thr³⁴² in helix 7 does not have a direct interaction with sumatriptan, it contributes to the selectivity of this receptor through an indirect mechanism. The hydrogen bond between O_γ-H of Thr³⁴² and the backbone C=O of Phe³³⁸ stabilizes a bent conformation of the helix that is formed due to the interaction between sumatriptan and Asp³³⁹ at one end and Tyr³⁴⁶ at the other end. The indirect mechanism may explain the small change in the affinity for the selective agonist sumatriptan of the receptor in which Thr³⁴² was mutated to asparagine.