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Cellular and Molecular Life Sciences

, Volume 74, Issue 2, pp 319–338 | Cite as

The crystal structure of the AgamOBP1•Icaridin complex reveals alternative binding modes and stereo-selective repellent recognition

  • Christina E. Drakou
  • Katerina E. Tsitsanou
  • Constantinos Potamitis
  • Dimitrios Fessas
  • Maria Zervou
  • Spyros E. ZographosEmail author
Original Article

Abstract

Anopheles gambiae Odorant Binding Protein 1 in complex with the most widely used insect repellent DEET, was the first reported crystal structure of an olfactory macromolecule with a repellent, and paved the way for OBP1-structure-based approaches for discovery of new host-seeking disruptors. In this work, we performed STD-NMR experiments to directly monitor and verify the formation of a complex between AgamOBP1 and Icaridin, an efficient DEET alternative. Furthermore, Isothermal Titration Calorimetry experiments provided evidence for two Icaridin-binding sites with different affinities (Kd = 0.034 and 0.714 mM) and thermodynamic profiles of ligand binding. To elucidate the binding mode of Icaridin, the crystal structure of AgamOBP1•Icaridin complex was determined at 1.75 Å resolution. We found that Icaridin binds to the DEET-binding site in two distinct orientations and also to a novel binding site located at the C-terminal region. Importantly, only the most active 1R,2S-isomer of Icaridin’s equimolar diastereoisomeric mixture binds to the AgamOBP1 crystal, providing structural evidence for the possible contribution of OBP1 to the stereoselectivity of Icaridin perception in mosquitoes. Structural analysis revealed two ensembles of conformations differing mainly in spatial arrangement of their sec-butyl moieties. Moreover, structural comparison with DEET indicates a common recognition mechanism for these structurally related repellents. Ligand interactions with both sites and binding modes were further confirmed by 2D 1H-15N HSQC NMR spectroscopy. The identification of a novel repellent-binding site in AgamOBP1 and the observed structural conservation and stereoselectivity of its DEET/Icaridin-binding sites open new perspectives for the OBP1-structure-based discovery of next-generation insect repellents.

Keywords

Anopheles gambiae Odorant binding protein Repellents Icaridin DEET Stereoselectivity 

Abbreviations

AgamOBP1

Odorant binding protein 1 from Anopheles gambiae

CquiOBP

Odorant binding protein from Culex quinquefasciatus

AaegOBP1

Odorant binding protein 1 from Aedes aegypti

OR

Odorant receptor

Icaridin

1:1 mixture of four racemic diastereoisomers of butan-2-yl 2-(2-hydroxyethyl)piperidine-1-carboxylate

DEET

N,N-diethyl-3-methylbenzamide

AI3-37220

1-[3-cyclohexen-1-ylcarbonyl]-2-methylpiperidine

6-MH

6-methyl-5-heptene-2-one

MOP

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

1-NPN

N-phenyl-1-naphthylamine

vdW

van der Waals

STD-NMR

Saturation transfer difference nuclear magnetic resonance spectroscopy

HSQC

Heteronuclear single quantum coherence

CSP

Chemical shift perturbation

Notes

Acknowledgments

We are grateful for the help and advice of Prof. Simona Golic Grdadolnik and Dr. Urška Zelenko (National Institute of Chemistry, Ljubljana, Slovenia) on the development of the expression protocol and their assistance in setting up the 3D NMR experiments for the sequence-specific assignment of 13C/15N-labeled AgamOBP1. We also thank Saltigo GmbH (Germany) for kindly providing Icaridin. We acknowledge the late Dr. Harald Biessmann and Dr. Marika F. Walter (Developmental Biology Center, University of California) for kindly providing the AgamOBP1 gene (GenBank™ Accession Number AF437884). We also would like to acknowledge Dr. Kostas Iatrou (Institute of Biosciences and Applications NCSR “Demokritos”, Greece), Dr. Elias Eliopoulos (Department of Biotechnology, Agricultural University of Athens, Greece) and Dr. Panagiotis Zoumpoulakis (Institute of Biology, Medicinal Chemistry and Biotechnology, NHRF, Greece) for helpful discussions. This work was supported by funding provided under the NSRF-Bilateral Greece-Turkey R&D cooperation 2013–2015 project “PREVENT” (GSRT 14TUR), co-Financed by the European Union and the Greek State, Ministry of Education and Religious Affairs/General Secretariat for Research and Technology (O. P. Competitiveness & Entrepreneurship (EPAN ΙΙ), ROP Macedonia–Thrace, ROP Crete and Aegean Islands, ROP Thessaly–Mainland Greece–Epirus, ROP Attica). It was also supported by the European Commission under the FP7- HEALTH-2007-2.3.2.9 project ‘‘ENAROMaTIC’’ (GA-222927) and the FP7-REGPOT-2009-1 Project ‘‘ARCADE’’ (GA-245866). Work at the Synchrotron Radiation Sources, MAX-lab, Lund, Sweden and ALBA, Barcelona, Spain, was supported by funding provided by the European Community’s Seventh Framework Programme (FP7/2007–2013) under BioStruct-X (Grant Agreement No. 283570).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest with the contents of this article.

Supplementary material

18_2016_2335_MOESM1_ESM.docx (1.6 mb)
Supplementary material 1 (DOCX 1597 kb)

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© Springer International Publishing 2016

Authors and Affiliations

  1. 1.Institute of Biology, Medicinal Chemistry and BiotechnologyNational Hellenic Research FoundationAthensGreece
  2. 2.Department of Food, Environmental and Nutritional Sciences (DeFENS)Università degli Studi di MilanoMilanItaly

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