Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif
| Autor: | Armin Buschauer, Christopher Pfleger, Timothy Clark, Jonas Kaindl, Holger Gohlke, Ralf C. Kling, Passainte Ibrahim, David Wifling |
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| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Agonist
Computational Chemistry | Hot Paper medicine.drug_class Phenylalanine Molecular Dynamics Simulation 010402 general chemistry 01 natural sciences Catalysis Molecular dynamics chemistry.chemical_compound Mice GPCR Catalytic Domain medicine rigidity analysis Animals Humans Active state Histamine H4 receptor Diphenylalanine Receptor G protein-coupled receptor Receptors Histamine H4 Binding Sites Full Paper 010405 organic chemistry Protein Stability Organic Chemistry General Chemistry basal activation Dipeptides Full Papers computational chemistry molecular dynamics 0104 chemical sciences chemistry ddc:540 Molecular mechanism Biophysics Mutagenesis Site-Directed |
| Zdroj: | Chemistry (Weinheim an Der Bergstrasse, Germany) |
| ISSN: | 1521-3765 0947-6539 |
| Popis: | 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. How does it work? In addition to ligand‐dependent G‐protein‐coupled receptor (GPCR) activation, which has been studied intensively, GPCRs can also be activated spontaneously in the absence of a ligand. This study highlights the mechanisms behind such basal GPCR activation by using the example of the H4R, a GPCR with extraordinarily high basal activity. |
| Databáze: | OpenAIRE |
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