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-HT1D 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-HT1D 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 gamma-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.