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

Vajravijayan, Senthilvadivel; Pletnev, Sergei; Pletnev, Vladimir Z.; Nandhagopal, Narayanasamy; Gunasekaran, Krishnasamy

doi:10.1002/ps.5063

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

Journal Article · Tue Jul 03 00:00:00 EDT 2018 · Pest Management Science

DOI:https://doi.org/10.1002/ps.5063· OSTI ID:1458794

Vajravijayan, Senthilvadivel ^[1]; Pletnev, Sergei ^[2]; Pletnev, Vladimir Z. ^[3];

^[1]; Gunasekaran, Krishnasamy ^[1]

Centre of Advanced Study in Crystallography and Biophysics University of Madras, Guindy Campus Chennai India
Macromolecular Crystallography Laboratory National Cancer Institute, and Basic Science Program, Leidos Biomedical Research Inc. Argonne IL USA
Shemyakin‐Ovchinnikov Institute of Bioorganic Chemistry Russian Academy of Sciences Moscow Russia

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

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Sponsoring Organization:: USDOE

Grant/Contract Number:: W‐31‐109‐Eng‐38

OSTI ID:: 1458794

Journal Information:: Pest Management Science, Journal Name: Pest Management Science Vol. 74 Journal Issue: 12; ISSN 1526-498X

Publisher:: Wiley Blackwell (John Wiley & Sons)Copyright Statement

Country of Publication:: United Kingdom

Language:: English

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