Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents
Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents
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DOI：
10.1007/s00018-011-0745-z
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发表时间：
2012-01-01
影响因子：
8
通讯作者：
Zographos, S. E.
中科院分区：
文献类型：
--
作者：
Tsitsanou, K. E.;Thireou, T.;Zographos, S. E.
昆虫气味结合蛋白（OBP）是嗅觉系统的第一个成分，能够遇到并结合各种来源发出的引诱剂和驱避剂气味，然后呈现给嗅觉受体，从而触发相关的信号转导级联，最终导致特定的生理和行为反应。对于疾病媒介，特别是食血蚊子，驱虫剂代表着预防寄生虫病的重要手段，因为它们可以减少媒介与人类之间的接触率。 OBP 是基于结构的合理方法的目标，用于发现具有所需特征的新驱虫剂或其他嗅觉抑制化合物。因此，我们进行了一项研究，以表征冈比亚按蚊（非洲疟疾蚊媒）OBP 与 N,N-二乙基间甲苯酰胺 (DEET) 的复合物的高分辨率晶体结构，避蚊胺是全球使用了 60 年来最有效的驱虫剂之一。我们发现避蚊胺通过利用大量非极性相互作用和一个氢键结合在长疏水隧道的边缘，这被认为对于避蚊胺的识别至关重要。基于实验确定的 AgamOBP1 对 DEET 的亲和力（K (d) 为 31.3 mu Ie）和我们的结构数据，我们模拟了该蛋白质与文献中报道的 29 个具有显着驱避活性的有希望的先导化合物的相互作用，并用四个排名较高的配体进行了荧光结合研究。我们的实验结果证实了建模预测，表明基于结构的建模可以促进具有增强的结合亲和力和选择性的新型驱虫剂的设计。
Insect odorant binding proteins (OBPs) are the first components of the olfactory system to encounter and bind attractant and repellent odors emanating from various sources for presentation to olfactory receptors, which trigger relevant signal transduction cascades culminating in specific physiological and behavioral responses. For disease vectors, particularly hematophagous mosquitoes, repellents represent important defenses against parasitic diseases because they effect a reduction in the rate of contact between the vectors and humans. OBPs are targets for structure-based rational approaches for the discovery of new repellent or other olfaction inhibitory compounds with desirable features. Thus, a study was conducted to characterize the high resolution crystal structure of an OBP of Anopheles gambiae, the African malaria mosquito vector, in complex with N,N-diethyl-m-toluamide (DEET), one of the most effective repellents that has been in worldwide use for six decades. We found that DEET binds at the edge of a long hydrophobic tunnel by exploiting numerous non-polar interactions and one hydrogen bond, which is perceived to be critical for DEET's recognition. Based on the experimentally determined affinity of AgamOBP1 for DEET (K (d) of 31.3 mu Ie) and our structural data, we modeled the interactions for this protein with 29 promising leads reported in the literature to have significant repellent activities, and carried out fluorescence binding studies with four highly ranked ligands. Our experimental results confirmed the modeling predictions indicating that structure-based modeling could facilitate the design of novel repellents with enhanced binding affinity and selectivity.