Abstract
The Histamine H-1-receptor (H1R), belonging to the amine receptor-class of family A of the G-protein coupled receptors (GPCRs) gets activated by agonists. The consequence is a conformational change of the receptor, which may involve the binding- pocket. So, for a good prediction of the binding- mode of an agonist, it is necessary to have knowledge about these conformational changes. Meanwhile ...
Abstract
The Histamine H-1-receptor (H1R), belonging to the amine receptor-class of family A of the G-protein coupled receptors (GPCRs) gets activated by agonists. The consequence is a conformational change of the receptor, which may involve the binding- pocket. So, for a good prediction of the binding- mode of an agonist, it is necessary to have knowledge about these conformational changes. Meanwhile some experimental data about the structural changes of GPCRs during activation exist. Based on homology modeling of the guinea-pig H1R (gpH(1)R), using the crystal structure of bovine rhodopsin as template, we performed several MD simulations with distance restraints in order to get an inactive and an active structure of the gpH1R. The calculations led to a Phe (6.44)/Trp (6.48)/Phe (6.52)-switch and linearization of the proline kinked transmembrane helix VI during receptor activation. Our calculations showed that the Trp 6.48/ Phe 6.52- switch induces a conformational change in Phe (6.44), which slides between transmembrane helices III and VI. Additionally we observed a hydrogen bond interaction of Ser(3.39) with Asn(7.45) in the inactive gpH(1)R, but because of a counterclockwise rotation of transmembrane helix III Ser(3.39) establishes a water-mediated hydrogen bond to Asp(2.50) in the active gpH(1)R. Additionally we simulated a possible mechanism for receptor activation with a modified LigPath- algorithm.
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