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Title: Crystal structure of a novel Kunitz type inhibitor, alocasin with anti‐ Aedes aegypti activity targeting midgut proteases

Abstract

Abstract BACKGROUND The pesticidal properties of many Kunitz‐type inhibitors have been reported previously; however, the mechanism of action is not well established. In this study, the activity of alocasin against Aedes aegypti is demonstrated and the structure–activity relationship of this Kunitz‐type inhibitor is explained through X‐ray structure analyses. RESULTS Alocasin was purified from mature rhizomes of Alocasia as a single polypeptide chain of ∼ 20 kDa. The structure at 2.5 Å resolution revealed a Kunitz‐type fold, but variation in the loop regions makes this structure unique; one loop with a single disulfide bridge is replaced by a long loop with two bridges. Alignment of homologous sequences revealed that this long loop contains a conserved Arg residue and modeling studies showed interaction with the catalytic Ser residue of trypsin‐like enzymes. The anti‐ Aedes aegypti activity of alocasin is examined and discussed in detail. The in vitro activity of alocasin against midgut proteases of Aedes aegypti showed profound inhibition. Further, morphological changes in larvae upon treatment with alocasin revealed its activity against Ae. aegypti . Docking studies of alocasin with trypsin (5G1), a midgut protease involved in the development cycle and blood meal digestion, illustrated its insecticidal activity. CONCLUSION The three‐dimensional structuremore » of alocasin was determined and its structure–function relationship established for its anti Ae. aegypti activity. © 2018 Society of Chemical Industry« less

Authors:
 [1];  [2];  [3]; ORCiD logo [1];  [1]
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  1. Centre of Advanced Study in Crystallography and Biophysics University of Madras, Guindy Campus Chennai India
  2. Macromolecular Crystallography Laboratory National Cancer Institute, and Basic Science Program, Leidos Biomedical Research Inc. Argonne IL USA
  3. Shemyakin‐Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences Moscow Russia
Publication Date:
Sponsoring Org.:
USDOE
OSTI Identifier:
1458794
Grant/Contract Number:  
W‐31‐109‐Eng‐38
Resource Type:
Publisher's Accepted Manuscript
Journal Name:
Pest Management Science
Additional Journal Information:
Journal Name: Pest Management Science Journal Volume: 74 Journal Issue: 12; Journal ID: ISSN 1526-498X
Publisher:
Wiley Blackwell (John Wiley & Sons)
Country of Publication:
United Kingdom
Language:
English

Citation Formats

Vajravijayan, Senthilvadivel, Pletnev, Sergei, Pletnev, Vladimir Z., Nandhagopal, Narayanasamy, and Gunasekaran, Krishnasamy. Crystal structure of a novel Kunitz type inhibitor, alocasin with anti‐ Aedes aegypti activity targeting midgut proteases. United Kingdom: N. p., 2018. Web. doi:10.1002/ps.5063.
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Vajravijayan, Senthilvadivel, Pletnev, Sergei, Pletnev, Vladimir Z., Nandhagopal, Narayanasamy, & Gunasekaran, Krishnasamy. Crystal structure of a novel Kunitz type inhibitor, alocasin with anti‐ Aedes aegypti activity targeting midgut proteases. United Kingdom. https://doi.org/10.1002/ps.5063
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Vajravijayan, Senthilvadivel, Pletnev, Sergei, Pletnev, Vladimir Z., Nandhagopal, Narayanasamy, and Gunasekaran, Krishnasamy. Tue . "Crystal structure of a novel Kunitz type inhibitor, alocasin with anti‐ Aedes aegypti activity targeting midgut proteases". United Kingdom. https://doi.org/10.1002/ps.5063.
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@article{osti_1458794,
title = {Crystal structure of a novel Kunitz type inhibitor, alocasin with anti‐ Aedes aegypti activity targeting midgut proteases},
author = {Vajravijayan, Senthilvadivel and Pletnev, Sergei and Pletnev, Vladimir Z. and Nandhagopal, Narayanasamy and Gunasekaran, Krishnasamy},
abstractNote = {Abstract BACKGROUND The pesticidal properties of many Kunitz‐type inhibitors have been reported previously; however, the mechanism of action is not well established. In this study, the activity of alocasin against Aedes aegypti is demonstrated and the structure–activity relationship of this Kunitz‐type inhibitor is explained through X‐ray structure analyses. RESULTS Alocasin was purified from mature rhizomes of Alocasia as a single polypeptide chain of ∼ 20 kDa. The structure at 2.5 Å resolution revealed a Kunitz‐type fold, but variation in the loop regions makes this structure unique; one loop with a single disulfide bridge is replaced by a long loop with two bridges. Alignment of homologous sequences revealed that this long loop contains a conserved Arg residue and modeling studies showed interaction with the catalytic Ser residue of trypsin‐like enzymes. The anti‐ Aedes aegypti activity of alocasin is examined and discussed in detail. The in vitro activity of alocasin against midgut proteases of Aedes aegypti showed profound inhibition. Further, morphological changes in larvae upon treatment with alocasin revealed its activity against Ae. aegypti . Docking studies of alocasin with trypsin (5G1), a midgut protease involved in the development cycle and blood meal digestion, illustrated its insecticidal activity. CONCLUSION The three‐dimensional structure of alocasin was determined and its structure–function relationship established for its anti Ae. aegypti activity. © 2018 Society of Chemical Industry},
doi = {10.1002/ps.5063},
journal = {Pest Management Science},
number = 12,
volume = 74,
place = {United Kingdom},
year = {Tue Jul 03 00:00:00 EDT 2018},
month = {Tue Jul 03 00:00:00 EDT 2018}
}
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