Cellular and Molecular Life Sciences

, Volume 69, Issue 2, pp 283–297 | Cite as

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

  • K. E. Tsitsanou
  • T. Thireou
  • C. E. Drakou
  • K. Koussis
  • M. V. Keramioti
  • D. D. Leonidas
  • E. Eliopoulos
  • K. Iatrou
  • S. E. ZographosEmail author
Research article


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.


Crystal structure Molecular modeling AgamOBP1 DEET Malaria 



Odorant binding protein 1 from Anopheles gambiae


Odorant receptor


Olfactory neuron












van der Waals



We acknowledge the late Dr. Harald Biessmann and Dr. Marika F. Walter (Developmental Biology Center, University of California), for kindly providing the AgamOBP1 gene. This work was supported by funding provided by the European Commission for the FP7- HEALTH-2007- project “ENAROMaTIC” (GA-222927), the FP7-REGPOT-2008-1 project “EUROSTRUCT” (GA-230146) and the FP7-REGPOT-2009-1 Project “ARCADE” (GA-245866). Work at the Synchrotron Radiation Sources, MAX-lab, Lund, Sweden and EMBL Hamburg Outstation, Germany, was supported by funding provided by the European Commission for the FP7 Research Infrastructure Action “ELISA” (European Light Sources Activities).

Supplementary material

18_2011_745_MOESM1_ESM.pdf (744 kb)
Supplementary material 1 (PDF 743 kb)


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Copyright information

© Springer Basel AG 2011

Authors and Affiliations

  • K. E. Tsitsanou
    • 1
  • T. Thireou
    • 2
  • C. E. Drakou
    • 1
  • K. Koussis
    • 3
  • M. V. Keramioti
    • 1
  • D. D. Leonidas
    • 4
  • E. Eliopoulos
    • 2
  • K. Iatrou
    • 3
  • S. E. Zographos
    • 1
    Email author
  1. 1.Institute of Organic and Pharmaceutical ChemistryNational Hellenic Research FoundationAthensGreece
  2. 2.Department of Agricultural BiotechnologyAgricultural University of AthensAthensGreece
  3. 3.Insect Molecular Genetics and Biotechnology Group, Institute of BiologyNCSR “Demokritos”AthensGreece
  4. 4.Department of Biochemistry and BiotechnologyUniversity of ThessalyLarissaGreece

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