Institute of Genetics, Biocenter, University at Cologne, Zülpicherstrasse 47a, 50674 Cologne, Germany.
Institute of Complex Systems (ICS-4), Research Center Jülich, 52428 Jülich, Germany.
Sci Rep. 2016 Jun 21;6:28359. doi: 10.1038/srep28359.
Olfaction poses one of the most complex ligand-receptor matching problems in biology due to the unparalleled multitude of odor molecules facing a large number of cognate olfactory receptors. We have recently deorphanized an olfactory receptor, TAAR13c, as a specific receptor for the death-associated odor cadaverine. Here we have modeled the cadaverine/TAAR13c interaction, exchanged predicted binding residues by site-directed mutagenesis, and measured the activity of the mutant receptors. Unexpectedly we observed a binding site for cadaverine at the external surface of the receptor, in addition to an internal binding site, whose mutation resulted in complete loss of activity. In stark contrast, elimination of the external binding site generated supersensitive receptors. Modeling suggests this site to act as a gate, limiting access of the ligand to the internal binding site and thereby downregulating the affinity of the native receptor. This constitutes a novel mechanism to fine-tune physiological sensitivity to socially relevant odors.
嗅觉面临着无与伦比的大量气味分子与大量同源嗅觉受体相匹配的问题，因此它构成了生物学中最复杂的配体-受体匹配问题之一。我们最近将一个嗅觉受体 TAAR13c 去孤儿化，将其鉴定为特定的死亡相关气味腐胺的受体。在这里，我们构建了腐胺/TAAR13c 相互作用模型，通过定点突变交换预测的结合残基，并测量了突变受体的活性。出乎意料的是，我们在受体的外表面除了观察到内部结合位点之外，还观察到腐胺的结合位点，该结合位点的突变导致完全丧失活性。相比之下，消除外部结合位点会产生超敏受体。建模表明该位点作为一个门，限制了配体进入内部结合位点的通道，从而降低了天然受体的亲和力。这构成了一种微调对社交相关气味的生理敏感性的新机制。
