<Emphasis Type="Italic">Anopheles gambiae</Emphasis> odorant binding protein crystal complex with the synthetic repellent DEET: implications for structure-based design of novel mosquito repellents |
| |
Authors: | K?E?Tsitsanou T?Thireou C?E?Drakou K?Koussis M?V?Keramioti D?D?Leonidas E?Eliopoulos K?Iatrou Email author" target="_blank">S?E?ZographosEmail author |
| |
Institution: | (1) Institute of Organic and Pharmaceutical Chemistry, National Hellenic Research Foundation, 48 Vas. Constantinou Ave., 11635 Athens, Greece;(2) Department of Agricultural Biotechnology, Agricultural University of Athens, Iera Odos 75, 11855 Athens, Greece;(3) Insect Molecular Genetics and Biotechnology Group, Institute of Biology, NCSR “Demokritos”, Agia Paraskevi, 15310 Athens, Greece;(4) Department of Biochemistry and Biotechnology, University of Thessaly, 26 Ploutonos Str., 41221 Larissa, Greece; |
| |
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. |
| |
Keywords: | |
本文献已被 PubMed SpringerLink 等数据库收录! |
|