Structural determinants of odorant recognition by the human olfactory receptors OR1A1 and OR1A2
Structural determinants of odorant recognition by the human olfactory receptors OR1A1 and OR1A2
复制标题
DOI：
10.1016/j.jsb.2007.04.013
复制
发表时间：
2007-09-01
影响因子：
3
通讯作者：
Krautwurst, Dietinar
中科院分区：
文献类型：
--
作者：
Schiniedeberg, Kristin;Shirokova, Elena;Krautwurst, Dietinar
气味剂与嗅觉受体的相互作用被认为是气味剂检测的第一步。然而，380 个人类嗅觉受体中只有 6 个被报道有配体，其气味识别的结构决定因素才刚刚开始出现。受与特定气味剂相互作用的氨基酸位置在直系同源物中保守，但在旁系同源物中可变的概念的指导，并基于对一组 22 个此类氨基酸位置的预测，我们结合了定点诱变、基于视紫红质的同源建模以及 HeLa/Olf 细胞中受体 OR1A1 和 OR1A2 的功能表达。我们发现（i）它们的气味特征以香茅萜类结构为中心，（ii）跨膜结构域3中的两个进化保守氨基酸残基对于OR I A I和小鼠直向同源物Olfr43对（S）-（-）-香茅醇的反应性是必需的，（iii）这两个位置的变化足以解释旁系同源物的差异（S）-（-）-香茅醇反应性OR1A1 和 OR1A2，以及 (iv) (S)-(-)-香茅醛和 (S)-(-)-香茅醇的相互作用位点在两种人类受体中都不同。我们的结果表明，嗅觉受体直向同源物的同源模型衍生的结合口袋内气味的方向是由进化保守的氨基酸位置定义的。 (c) 2007 年，爱思唯尔公司出版。
An interaction of odorants with olfactory receptors is thought to be the initial step in odorant detection. However, ligands have been reported for only 6 out of 380 human olfactory receptors, with their structural determinants of odorant recognition just beginning to emerge. Guided by the notion that amino acid positions that interact with specific odorants would be conserved in orthologs, but variable in paralogs, and based on the prediction of a set of 22 of such amino acid positions, we have combined site-directed mutagenesis, rhodopsin-based homology modelling, and functional expression in HeLa/Olf cells of receptors OR1A1 and OR1A2. We found that (i) their odorant profiles are centred around citronellic terpenoid structures, (ii) two evolutionary conserved amino acid residues in transmembrane domain 3 are necessary for the responsiveness of OR I A I and the mouse ortholog Olfr43 to (S)-(-)-citronellol, (iii) changes at these two positions are sufficient to account for the differential (S)-(-)-citronellol responsiveness of the paralogs OR1A1 and OR1A2, and (iv) the interaction sites for (S)-(-)-citronellal and (S)-(-)-citronellol differ in both human receptors. Our results show that the orientation of odorants within a homology modelling-derived binding pocket of olfactory receptor orthologs is defined by evolutionary conserved amino acid positions. (c) 2007 Published by Elsevier Inc.