Cellular and Molecular Life Sciences

, Volume 69, Issue 2, pp 283–297

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

Authors

  • K. E. Tsitsanou
    • Institute of Organic and Pharmaceutical ChemistryNational Hellenic Research Foundation
  • T. Thireou
    • Department of Agricultural BiotechnologyAgricultural University of Athens
  • C. E. Drakou
    • Institute of Organic and Pharmaceutical ChemistryNational Hellenic Research Foundation
  • K. Koussis
    • Insect Molecular Genetics and Biotechnology Group, Institute of BiologyNCSR “Demokritos”
  • M. V. Keramioti
    • Institute of Organic and Pharmaceutical ChemistryNational Hellenic Research Foundation
  • D. D. Leonidas
    • Department of Biochemistry and BiotechnologyUniversity of Thessaly
  • E. Eliopoulos
    • Department of Agricultural BiotechnologyAgricultural University of Athens
  • K. Iatrou
    • Insect Molecular Genetics and Biotechnology Group, Institute of BiologyNCSR “Demokritos”
    • Institute of Organic and Pharmaceutical ChemistryNational Hellenic Research Foundation
Research article

DOI: 10.1007/s00018-011-0745-z

Cite this article as:
Tsitsanou, K.E., Thireou, T., Drakou, C.E. et al. Cell. Mol. Life Sci. (2012) 69: 283. doi:10.1007/s00018-011-0745-z

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 (Kd 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

Crystal structureMolecular modelingAgamOBP1DEETMalaria

Abbreviations

AgamOBP1

Odorant binding protein 1 from Anopheles gambiae

OR

Odorant receptor

ON

Olfactory neuron

DEET

N,N-Diethyl-m-toluamide

1-NPN

N-Phenyl-1-naphthylamine

IPTG

Isopropyl-galacto-pyranoside

MOP

(5R,6S)-6-Acetoxy-5-hexadecanolide

TLS

Translation/libration/screw

vdW

van der Waals

Supplementary material

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

Copyright information

© Springer Basel AG 2011