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000849921 1001_ $$0P:(DE-HGF)0$$aSharma, Kanika$$b0$$eCorresponding author
000849921 245__ $$aFull rescue of an inactive olfactory receptor mutant by elimination of an allosteric ligand-gating site
000849921 260__ $$aLondon$$bNature Publishing Group$$c2018
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000849921 520__ $$aLigand-gating has recently been proposed as a novel mechanism to regulate olfactory receptor sensitivity. TAAR13c, the zebrafish olfactory receptor activated by the death-associated odor cadaverine, appears to possess an allosteric binding site for cadaverine, which was assumed to block progress of the ligand towards the internal orthosteric binding-and-activation site. Here we have challenged the suggested gating mechanism by modeling the entry tunnel for the ligand as well as the ligand path inside the receptor. We report an entry tunnel, whose opening is blocked by occupation of the external binding site by cadaverine, confirming the hypothesized gating mechanism. A multistep docking algorithm suggested a plausible path for cadaverine from the allosteric to the orthosteric binding-and-activation site. Furthermore we have combined a gain-of-function gating site mutation and a loss-of-function internal binding site mutation in one recombinant receptor. This receptor had almost wildtype ligand affinities, consistent with modeling results that showed localized effects for each mutation. A novel mutation of the suggested gating site resulted in increased receptor ligand affinity. In summary both the experimental and the modeling results provide further evidence for the proposed gating mechanism, which surprisingly exhibits pronounced similarity to processes described for some metabotropic neurotransmitter receptors.
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000849921 7001_ $$0P:(DE-Juel1)131909$$aBalfanz, Sabine$$b1
000849921 7001_ $$0P:(DE-Juel1)131911$$aBaumann, Arnd$$b2
000849921 7001_ $$0P:(DE-HGF)0$$aKorsching, Sigrun$$b3$$eCorresponding author
000849921 773__ $$0PERI:(DE-600)2615211-3$$a10.1038/s41598-018-27790-7$$gVol. 8, no. 1, p. 9631$$n1$$p9631$$tScientific reports$$v8$$x2045-2322$$y2018
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