The agonistic binding site at the histamine H₂ receptor. I. Theoretical investigations of histamine binding to an oligopeptide mimicking a part of the fifth transmembrane α-helix

Summary

Mutation studies on the histamine H₂ receptor were reported by Gantz et al. [J. Biol. Chem., 267 (1992) 20840], which indicate that both the mutation of the fifth transmembrane Asp¹⁸⁶ (to Ala¹⁸⁶) alone or in combination with Thr¹⁹⁰ (to Ala¹⁹⁰) maintained, albeit partially, the cAMP response to histamine. Recently, we have shown that histamine binds to the histamine H₂ receptor as a monocation in its proximal tautomeric form, and, moreover, we suggested that a proton is donated from the receptor towards the tele-position of the agonist, thereby triggering the biological effect [Nederkoorn et al., J. Mol. Graph., 12 (1994) 242; Eriks et al., Mol. Pharmacol., 44 (1993) 886]. These findings result in a close resemblance with the catalytic triad (consisting of Ser, His and Asp) found in serine proteases. Thr¹⁹⁰ resembles a triad's serine residue closely, and could also act as a proton donor. However, the mutation of Thr¹⁹⁰ to Ala¹⁹⁰ — the latter is unable to function as a proton donor — does not completely abolish the agonistic cAMP response. At the fifth transmembrane α-helix of the histamine H₂ receptor near the extracellular surface, another amino acid is present, i.e. Tyr¹⁸², so an alternative couple of amino acids, Tyr¹⁸² and Asp¹⁸⁶, could constitute the histamine binding site at the fifth α-helix instead of the (mutated) couple Asp¹⁸⁶ and Thr¹⁹⁰. In the first part of our present study, this hypothesis is investigated with the aid of an oligopeptide with an α-helical backbone, which represents a part of the fifth transmembrane helix. Both molecular mechanics and ab initio data lead to the conclusion that the Tyr¹⁸²/Asp¹⁸⁶ couple is most likely to act as the binding site for the imidazole ring present in histamine.