This title appears in the Scientific Report :
2019
Please use the identifier:
http://dx.doi.org/10.1002/chem.201902801 in citations.
Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif
Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif
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‐time‐scale molecular‐dynamics simulation...
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Personal Name(s): | Wifling, David |
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Pfleger, Christopher / Kaindl, Jonas / Ibrahim, Paissante / Kling, Ralf / Buschauer, Armin / Gohlke, Holger (Corresponding author) / Clark, Tim (Corresponding author) | |
Contributing Institute: |
Strukturbiochemie; ICS-6 Jülich Supercomputing Center; JSC John von Neumann - Institut für Computing; NIC |
Published in: | Chemistry - a European journal, 25 (2019) 64, S. 14613-14624 |
Imprint: |
Weinheim
Wiley-VCH
2019
|
PubMed ID: |
31498478 |
DOI: |
10.1002/chem.201902801 |
Document Type: |
Journal Article |
Research Program: |
Forschergruppe Gohlke Computational Science and Mathematical Methods |
Publikationsportal JuSER |
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‐time‐scale 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 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. |