Preferential Binding of an Odor Within Olfactory Receptors: A Precursor to Receptor Activation
Preferential Binding of an Odor Within Olfactory Receptors: A Precursor to Receptor Activation
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DOI：
10.1093/chemse/bjt060
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发表时间：
2014-02-01
期刊：
影响因子：
3.5
通讯作者：
Crasto, Chiquito J.
中科院分区：
文献类型：
--
作者：
Lai, Peter C.;Guida, Brandon;Crasto, Chiquito J.
使用计算方法，允许在分子水平上的机械性洞察，我们探索了2个小鼠嗅觉受体(OR)气味的相互作用，S79和S86。这两个OR之前都已在实验和功能上进行了表征。使用的气味主要是羧酸，其链长、主碳原子链上的取代基和不饱和度都不同。这些气味引起了两种ORs不同的激活反应。我们的研究表明，这两种受体都有两个不同的结合部位。2个位点中有1个的优先结合与OR激活有关。OR S79的激活剂--正庚酸、辛酸和OR S79的激活剂，以及OR-S86的非激动剂--正庚酸优先结合在跨膜(TMS[螺旋结构域])III、IV、V和VI结合的区域。非刺激性气味物质庚醇(针对S79)和庚酸(针对S86)则更有可能结合在TMS I、II、III和VII结合的区域。纳秒级分子动力学模拟对接的OR型气味复合体的生理相关条件使我们能够定量评估单个OR氨基酸在气味结合中的作用。模拟过程中的氨基酸气味接触图和距离测定支持了我们的结论。
Using computational methods, which allow mechanistic insights at a molecular level, we explored the olfactory receptor (OR)odor interactions for 2 mouse ORs, S79 and S86. Both ORs have been previously experimentally, functionally characterized. The odors used were mostly carboxylic acids, which differed in chain length, substituents on the primary carbon atom-chain and degree of unsaturation. These odors elicited varied activation responses from both ORs. Our studies revealed that both receptors have 2 distinct binding sites. Preferential binding in 1 of the 2 sites is correlated with OR activation. The activating odorants: nonanedioic acid, heptanoic acid, and octanoic acid for OR S79 and nonanoic acid for OR S86 preferentially bind in the region bound by transmembranes (TMs [helical domains]) III, IV, V, and VI. The non excitatory odorants heptanol for S79 and heptanoic acid for S86 showed a greater likelihood of binding in the region bound by TMs I, II, III, and VII. Nanosecond-scale molecular dynamics simulations of the physiologically relevant conditions of docked ORodorant complexes enabled us to quantitatively assess the roles of individual OR amino acids in odor binding. Amino acidodorant contact maps and distance determinations over the course of the simulations lend support to our conclusions.