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Analysis of the activation mechanism of the guinea-pig Histamine H1-receptor

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Abstract

The Histamine H1-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 (gpH1R), 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 Phe6.44/Trp6.48/Phe6.52-switch and linearization of the proline kinked transmembrane helix VI during receptor activation. Our calculations showed that the Trp6.48/Phe6.52-switch induces a conformational change in Phe6.44, which slides between transmembrane helices III and VI. Additionally we observed a hydrogen bond interaction of Ser3.39 with Asn7.45 in the inactive gpH1R, but because of a counterclockwise rotation of transmembrane helix III Ser3.39 establishes a water-mediated hydrogen bond to Asp2.50 in the active gpH1R. Additionally we simulated a possible mechanism for receptor activation with a modified LigPath-algorithm.

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Authors and Affiliations

  1. Department of Pharmaceutical and Medicinal Chemistry, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    Andrea Straßer

  2. EDV-Referent, Faculty of Chemistry and Pharmacy, University of Regensburg, Regensburg, Germany

    Hans-Joachim Wittmann

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  1. Andrea Straßer
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  2. Hans-Joachim Wittmann
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Correspondence to Andrea Straßer.

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Straßer, A., Wittmann, HJ. Analysis of the activation mechanism of the guinea-pig Histamine H1-receptor. J Comput Aided Mol Des 21, 499–509 (2007). https://doi.org/10.1007/s10822-007-9131-1

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  • DOI: https://doi.org/10.1007/s10822-007-9131-1

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