Εξειδίκευση τύπου :	Άρθρο σε επιστημονικό περιοδικό
Τίτλος:	The crystal structure of the AgamOBP1•Icaridin complex reveals alternative binding modes and stereo-selective repellent recognition
Δημιουργός/Συγγραφέας:	Drakou C.E. Tsitsanou K.E. Potamitis C. Fessas D. [EL] Ζερβού, Μαρία[EN] Zervou, Maria [EL] Ζωγράφος, Σπύρος Ε.[EN] Zographos, Spyros E.
Εκδότης:	Birkhauser Verlag AG
Ημερομηνία:	2016
Γλώσσα:	Αγγλικά
ISSN:	1420-682X
DOI:	10.1007/s00018-016-2335-6
Άλλο:	PubMed ID: 27535661
Περίληψη:	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.
Τίτλος πηγής δημοσίευσης:	Cellular and Molecular Life Sciences
Τόμος/Κεφάλαιο:	74
Τεύχος:	2
Σελίδες:	319-338
Θεματική Κατηγορία:	[EL] Βιολογία (Γενικά)[EN] Biology (General) [EL] Χημεία (Γενικά)[EN] Chemistry (General)
Λέξεις-Κλειδιά:	Anopheles gambiae DEET Icaridin Odorant binding protein Repellents Stereoselectivity
Αξιολόγηση από ομότιμους (peer reviewed):	Ναι
Κάτοχος πνευματικών δικαιωμάτων:	© 2016, Springer International Publishing.
Σημειώσεις:	Seventh Framework Programme, FP7: 283570, GA-222927, GA-245866; European Commission, EC. 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). 13 15
Εμφανίζεται στις συλλογές:	Ινστιτούτο Χημικής Βιολογίας - Επιστημονικό έργο