TY  - JOUR
AU  - Wifling, David
AU  - Pfleger, Christopher
AU  - Kaindl, Jonas
AU  - Ibrahim, Paissante
AU  - Kling, Ralf
AU  - Buschauer, Armin
AU  - Gohlke, Holger
AU  - Clark, Tim
TI  - Basal Histamine H4 Receptor Activation: Agonist Mimicry by the Diphenylalanine Motif
JO  - Chemistry - a European journal
VL  - 25
IS  - 64
SN  - 1521-3765
CY  - Weinheim
PB  - Wiley-VCH
M1  - FZJ-2019-04708
SP  - 14613-14624
PY  - 2019
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:31498478
UR  - <Go to ISI:>//WOS:000490306500001
DO  - DOI:10.1002/chem.201902801
UR  - https://juser.fz-juelich.de/record/865162
ER  -