The agonistic binding site at the histamine H receptor. II. Theoretical investigations of histamine binding to receptor models of the seven α-helical transmembrane domain

In the first part (pp. 461-478 in this issue) of this study regarding the histamine H receptor agonistic binding site, the best possible interactions of histamine with an α-helical oligopeptide, mimicking a part of the fifth transmembrane α-helical domain (TM5) of the histamine H receptor, were considered. It was established that histamine can only bind via two H-bonds with a pure α-helical TM5, when the binding site consists of Tyr/Asp and not of the Asp/Thr couple. In this second part, two particular three-dimensional models of G-protein-coupled receptors previously reported in the literature are compared in relation to agonist binding at the histamine H receptor. The differences between these two receptor models are discussed in relation to the general benefits and limitations of such receptor models. Also the pros and cons of simplifying receptor models to a relatively easy-to-deal-with oligopeptide for mimicking agonistic binding to an agonistic binding site are addressed. Within complete receptor models, the simultaneous interaction of histamine with both TM3 and TM5 can be analysed. The earlier suggested three-point interaction of histamine with the histamine H receptor can be explored. Our results demonstrate that a three-point interaction cannot be established for the Asp/Asp/Thr binding site in either of the investigated receptor models, whereas histamine can form three H-bonds in case the agonistic binding site is constituted by the Asp/Tyr/Asp triplet. Furthermore, this latter triplet is seen to be able to accommodate a series of substituted histamine analogues with known histamine H agonistic activity as well. © 1996 ESCOM Science Publishers B.V.