The Mouse Eugenol Odorant Receptor: Structural and Functional Plasticity of a Broadly Tuned Odorant Binding Pocket
The Mouse Eugenol Odorant Receptor: Structural and Functional Plasticity of a Broadly Tuned Odorant Binding Pocket
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DOI：
10.1021/bi1017396
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发表时间：
2011-02-08
期刊：
影响因子：
2.9
通讯作者：
Pick, Horst
中科院分区：
文献类型：
--
作者：
Baud, Olivia;Etter, Sylvain;Pick, Horst
气味物质与它们的嗅觉受体(ORs)的分子相互作用对于哺乳动物嗅觉系统利用有限的受体检测和区分各种气味的能力是至关重要的。一种特定的OR是如何结合和区分不同的气味分子的，在结构上仍然很大程度上是未知的。在这里，我们研究了小鼠丁香酚受体(MOR-EG)的这个问题。通过筛选一个大的气味物库，我们发现了在异种哺乳动物细胞中激活该受体的广泛的化学结构。有效的激动剂包括(I)苯、(Ii)环己烷或(Iii)被醇、醛、酮、醚或酯化羧基取代的多环结构。为了检测受体内与特定结合气味分子接触的氨基酸，我们研究了不同的MOR-EG点突变是如何被为野生型受体发现的不同气味激动剂激活的。我们鉴定了11个氨基酸作为受体配体结合口袋的一部分。分子建模预测，其中10个残基位于跨膜螺旋TM3-TM6中，1个残基位于TM2和TM3之间的细胞外环中。这些氨基酸参与气味结合，其重要性因气味类型而异，揭示了配体-受体相互作用的功能“指纹”。
Molecular interactions of odorants with their olfactory receptors (ORs) are of central importance for the ability of the mammalian olfactory system to detect and discriminate a vast variety of odors with a limited set of receptors. How a particular OR binds and distinguishes different odorant molecules remains largely unknown on a structural basis. Here we investigated this question for the mouse eugenol receptor (mOR-EG). By screening a large odorant library, we discovered a wide range of chemical structures activating the receptor in heterologous mammalian cells. Potent agonists comprise (i) benzene, (ii) cyclohexane, or (iii) polycyclic structures substituted with alcohol, aldehyde, keto, ether, or esterified carboxylic groups. To detect those amino acids within the receptor that are in contact with a particular bound odorant molecule, we investigated how distinct mOR-EG point mutants were activated by the different odorant agonists found for the wild-type receptor. We identified 11 amino acids as a part of the receptor's ligand binding pocket. Molecular modeling predicted 10 of these residues in transmembrane helices TM3-TM6 and one in the extracellular loop between TM2 and TM3. These amino acids participate in odorant binding with variable importance depending on the type of odorant, revealing functional "fingerprints" of ligand-receptor interactions.