Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: Implications for structure-based design of novel mosquito repellents

dc.contributor.author	Tsitsanou, KE	en
dc.contributor.author	Thireou, T	en
dc.contributor.author	Drakou, CE	en
dc.contributor.author	Koussis, K	en
dc.contributor.author	Keramioti, MV	en
dc.contributor.author	Leonidas, DD	en
dc.contributor.author	Eliopoulos, E	en
dc.contributor.author	Iatrou, K	en
dc.contributor.author	Zographos, SE	en
dc.date.accessioned	2014-06-06T06:51:38Z
dc.date.available	2014-06-06T06:51:38Z
dc.date.issued	2012	en
dc.identifier.issn	1420682X	en
dc.identifier.uri	http://dx.doi.org/10.1007/s00018-011-0745-z	en
dc.identifier.uri	http://62.217.125.90/xmlui/handle/123456789/5610
dc.subject	AgamOBP1	en
dc.subject	Crystal structure	en
dc.subject	DEET	en
dc.subject	Malaria	en
dc.subject	Molecular modeling	en
dc.subject.other	AgamOBP1 protein	en
dc.subject.other	binding protein	en
dc.subject.other	diethyltoluamide	en
dc.subject.other	insect repellent	en
dc.subject.other	unclassified drug	en
dc.subject.other	Anopheles gambiae	en
dc.subject.other	article	en
dc.subject.other	binding affinity	en
dc.subject.other	binding site	en
dc.subject.other	complex formation	en
dc.subject.other	crystal structure	en
dc.subject.other	hydrogen bond	en
dc.subject.other	molecular docking	en
dc.subject.other	molecular model	en
dc.subject.other	nonhuman	en
dc.subject.other	nucleotide sequence	en
dc.subject.other	protein interaction	en
dc.subject.other	structure analysis	en
dc.subject.other	Animals	en
dc.subject.other	Anopheles gambiae	en
dc.subject.other	DEET	en
dc.subject.other	Drug Design	en
dc.subject.other	Female	en
dc.subject.other	Hydrogen Bonding	en
dc.subject.other	Insect Repellents	en
dc.subject.other	Male	en
dc.subject.other	Models, Molecular	en
dc.subject.other	Protein Conformation	en
dc.subject.other	Receptors, Odorant	en
dc.subject.other	Anopheles gambiae	en
dc.subject.other	Hexapoda	en
dc.title	Anopheles gambiae odorant binding protein crystal complex with the synthetic repellent DEET: Implications for structure-based design of novel mosquito repellents	en
heal.type	journalArticle	en
heal.identifier.primary	10.1007/s00018-011-0745-z	en
heal.publicationDate	2012	en
heal.abstract	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 μΜ) 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. © 2011 Springer Basel AG.	en
heal.journalName	Cellular and Molecular Life Sciences	en
dc.identifier.issue	2	en
dc.identifier.volume	69	en
dc.identifier.doi	10.1007/s00018-011-0745-z	en
dc.identifier.spage	283	en
dc.identifier.epage	297	en