Journal Article

FZJ-2018-04017

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Full rescue of an inactive olfactory receptor mutant by elimination of an allosteric ligand-gating site

Sharma, K. (Corresponding author) ; Balfanz, S.FZJ* ; Baumann, A.FZJ* ; Korsching, S. (Corresponding author)

2018
Nature Publishing Group London

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Please use a persistent id in citations: http://hdl.handle.net/2128/19259  doi:10.1038/s41598-018-27790-7

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.

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Contributing Institute(s):

1. Zelluläre Biophysik (ICS-4)

Research Program(s):

1. 552 - Engineering Cell Function (POF3-552) (POF3-552)

Appears in the scientific report 2018

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