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@ARTICLE{Sharma:849921,
author = {Sharma, Kanika and Balfanz, Sabine and Baumann, Arnd and
Korsching, Sigrun},
title = {{F}ull rescue of an inactive olfactory receptor mutant by
elimination of an allosteric ligand-gating site},
journal = {Scientific reports},
volume = {8},
number = {1},
issn = {2045-2322},
address = {London},
publisher = {Nature Publishing Group},
reportid = {FZJ-2018-04017},
pages = {9631},
year = {2018},
abstract = {Ligand-gating has recently been proposed as a novel
mechanism to regulate olfactory receptor sensitivity.
TAAR13c, the zebrafish olfactory receptor activated by the
death-associated odor cadaverine, appears to possess an
allosteric binding site for cadaverine, which was assumed to
block progress of the ligand towards the internal
orthosteric binding-and-activation site. Here we have
challenged the suggested gating mechanism by modeling the
entry tunnel for the ligand as well as the ligand path
inside the receptor. We report an entry tunnel, whose
opening is blocked by occupation of the external binding
site by cadaverine, confirming the hypothesized gating
mechanism. A multistep docking algorithm suggested a
plausible path for cadaverine from the allosteric to the
orthosteric binding-and-activation site. Furthermore we have
combined a gain-of-function gating site mutation and a
loss-of-function internal binding site mutation in one
recombinant receptor. This receptor had almost wildtype
ligand affinities, consistent with modeling results that
showed localized effects for each mutation. A novel mutation
of the suggested gating site resulted in increased receptor
ligand affinity. In summary both the experimental and the
modeling results provide further evidence for the proposed
gating mechanism, which surprisingly exhibits pronounced
similarity to processes described for some metabotropic
neurotransmitter receptors.},
cin = {ICS-4},
ddc = {000},
cid = {I:(DE-Juel1)ICS-4-20110106},
pnm = {552 - Engineering Cell Function (POF3-552)},
pid = {G:(DE-HGF)POF3-552},
typ = {PUB:(DE-HGF)16},
pubmed = {pmid:29941999},
UT = {WOS:000436077800052},
doi = {10.1038/s41598-018-27790-7},
url = {https://juser.fz-juelich.de/record/849921},
}