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 recept or subtypes suggest that a threonine in the seventh transmembrane heli x may be responsible for the selectivity of these receptors. A molecul ar dynamics simulation of a three-dimensional model of the 5-HT1D rece ptor interacting with a selective agonist, sumatriptan, shows that, al though Thr342 in helix 7 does not have a direct interaction with sumat riptan, 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 heli x that is formed due to the interaction between sumatriptan and Asp339 at one end and Tyr346 at the other end. The indirect mechanism may ex plain the small change in the affinity for the selective agonist sumat riptan of the receptor in which Thr342 was mutated to asparagine.