Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif |
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Authors: | Dr David Wifling Dr Christopher Pfleger Jonas Kaindl Passainte Ibrahim Dr Ralf C Kling Prof?Dr Armin Buschauer Prof?Dr Holger Gohlke Prof?Dr Timothy Clark |
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Institution: | 1. Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany;2. Institute for Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitätsstr. 1, 40225 Düsseldorf, Germany;3. Computer Chemistry Center, Department of Chemistry and Pharmacy, University of Erlangen-Nürnberg, Nägelsbachstr. 25, 91052 Erlangen, Germany;4. Department of Pharmaceutical/Medicinal Chemistry II, Institute of Pharmacy, University of Regensburg, Universitätsstr. 31, 93053 Regensburg, Germany
Deceased, July 18, 2017. |
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Abstract: | Histamine H4 receptor (H4R) orthologues are G-protein-coupled receptors (GPCRs) that exhibit species-dependent basal activity. In contrast to the basally inactive mouse H4R (mH4R), human H4R (hH4R) shows a high degree of basal activity. We have performed long-timescale molecular dynamics simulations and rigidity analyses on wild-type hH4R, the experimentally characterized hH4R variants S179M, F169V, F169V+S179M, F168A, and on mH4R to investigate the molecular nature of the differential basal activity. H4R variant-dependent differences between essential motifs of GPCR activation and structural stabilities correlate with experimentally determined basal activities and provide a molecular explanation for the differences in basal activation. Strikingly, during the MD simulations, F16945.55 dips into the orthosteric binding pocket only in the case of hH4R, thus adopting the role of an agonist and contributing to the stabilization of the active state. The results shed new light on the molecular mechanism of basal H4R activation that are of importance for other GPCRs. |
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Keywords: | basal activation computational chemistry GPCR molecular dynamics rigidity analysis |
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