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Molecular modeling of lanthionine synthetase component C-like protein 2: a potential target for the discovery of novel type 2 diabetes prophylactics and therapeutics

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Abstract

The rates of type 2 diabetes (T2D) are rising to epidemic proportions in the US and worldwide. While current T2D medications are efficacious, significant side effects have limited their use and availability. Our laboratory has discovered that abscisic acid (ABA) exerts anti-diabetic effects, in part, by activating peroxisome proliferator-activated receptor γ (PPAR γ). However, since ABA does not bind to the ligand-binding domain (LBD) of PPAR γ, the mechanism of activation of PPAR γ by ABA remains unknown. Lanthionine synthetase component C-like protein 2 (LANCL2) was predicted to be a novel target for the binding and signaling of ABA in human granulocytes and rat insulinoma cells. The goal of this study was to determine whether LANCL2 is a molecular target of ABA and other PPAR γ agonists. To this end we performed homology modeling to construct a three-dimensional structure of LANCL2 using the crystal structure of LANCL1 as a template. Our molecular docking studies predicted that ABA and other PPAR γ agonists (e.g., rosiglitazone and pioglitazone) share a binding site on the surface of LANCL2. The identification of a binding site for PPAR γ agonists will facilitate the high-throughput virtual screening of large compound libraries and may shed new light on alternative mechanisms of PPAR γ activation.

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Acknowledgments

Supported by award number 5R01AT4308 of the National Center for Complementary and Alternative Medicine at the National Institutes of Health awarded to J.B.-R., European Commission grant number 224836, the Ramon y Cajal Program and funds from the Nutritional Immunology and Molecular Nutrition Laboratory.

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Authors and Affiliations

  1. Genetics, Bioinformatics, and Computational Biology Program, Virginia Polytechnic Institute and State University, Blacksburg, VA, 24061, USA

    Pinyi Lu & Stephanie N. Lewis

  2. Nutritional Immunology and Molecular Nutrition Laboratory, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Washington Street 0477, Blacksburg, VA, 24061, USA

    Pinyi Lu, Stephanie N. Lewis, Raquel Hontecillas & Josep Bassaganya-Riera

  3. Department of Biochemistry, Virginia Polytechnic Institute and State University, 201 Engel Hall 0308, Blacksburg, VA, 24061, USA

    Pinyi Lu, David R. Bevan & Stephanie N. Lewis

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  1. Pinyi Lu
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  2. David R. Bevan
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  3. Stephanie N. Lewis
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  4. Raquel Hontecillas
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  5. Josep Bassaganya-Riera
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Correspondence to Josep Bassaganya-Riera.

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Lu, P., Bevan, D.R., Lewis, S.N. et al. Molecular modeling of lanthionine synthetase component C-like protein 2: a potential target for the discovery of novel type 2 diabetes prophylactics and therapeutics. J Mol Model 17, 543–553 (2011). https://doi.org/10.1007/s00894-010-0748-y

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  • DOI: https://doi.org/10.1007/s00894-010-0748-y

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