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@ARTICLE{Wifling:865162,
author = {Wifling, David and Pfleger, Christopher and Kaindl, Jonas
and Ibrahim, Paissante and Kling, Ralf and Buschauer, Armin
and Gohlke, Holger and Clark, Tim},
title = {{B}asal {H}istamine {H}4 {R}eceptor {A}ctivation: {A}gonist
{M}imicry by the {D}iphenylalanine {M}otif},
journal = {Chemistry - a European journal},
volume = {25},
number = {64},
issn = {1521-3765},
address = {Weinheim},
publisher = {Wiley-VCH},
reportid = {FZJ-2019-04708},
pages = {14613-14624},
year = {2019},
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‐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.},
cin = {NIC / JSC / ICS-6},
ddc = {540},
cid = {I:(DE-Juel1)NIC-20090406 / I:(DE-Juel1)JSC-20090406 /
I:(DE-Juel1)ICS-6-20110106},
pnm = {511 - Computational Science and Mathematical Methods
(POF3-511) / Forschergruppe Gohlke $(hkf7_20170501)$},
pid = {G:(DE-HGF)POF3-511 / $G:(DE-Juel1)hkf7_20170501$},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:31498478},
UT = {WOS:000490306500001},
doi = {10.1002/chem.201902801},
url = {https://juser.fz-juelich.de/record/865162},
}