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Predicting functional residues of the Solanum lycopersicum aspartic protease inhibitor (SLAPI) by combining sequence and structural analysis with molecular docking

Journal of Molecular Modeling volume 18, pages 2673–2687 (2012)Cite this article

Abstract

The Solanum lycopersicum aspartic protease inhibitor (SLAPI), which belongs to the STI-Kunitz family, is an effective inhibitor of the aspartic proteases human cathepsin D and Saccharomyces proteinase A. However, in contrast with the large number of studies on the inhibition mechanism of the serine proteases by the STI-Kunitz inhibitors, the structural aspects of the inhibition mechanism of aspartic proteases from this family of inhibitors are poorly understood. In the present study, we have combined sequence and structural analysis methods with protein-protein docking to gain a better understanding of the SLAPI inhibition mechanism of the proteinase A. The results suggest that: i) SLAPI loop L9 may be involved in the inhibitor interaction with the proteinase A´s active site, and ii) the residues I144, V148, L149, P151, F152 and R154 are implicated in the difference in the potency shown previously by SLAPI and another STI-Kunitz inhibitor isolated from Solanum tuberosum to inhibit proteinase A. These results will be useful in the design of site directed mutagenesis experiments to understand more thoroughly the aspartic protease inhibition mechanism of SLAPI and other related STI-Kunitz inhibitors.

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Acknowledgments

This research was supported by the International Foundation for Science (IFS), Stockholm, Sweden, through a grant to YG (grant No. F/4927-1). YG would also like to thank MSc. Alexandra Nárvaez from the Pontificia Universidad Católica del Ecuador (PUCE) for providing lab facilities.

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Author notes

  1. Tirso Pons

    Present address: Structural Biology and Biocomputing Programme, Spanish National Cancer Research Centre (CNIO), C/Melchor Fernández Almagro 3, Madrid, 28029, Spain

Authors and Affiliations

  1. Centro de Estudio de Proteínas (CEP), Facultad de Biología, Universidad de La Habana, Calle 25 No. 455 % J e I, Vedado, CP 10400, La Habana, Cuba

    Yasel Guerra, Pedro A. Valiente & Tirso Pons

  2. Cardiff School of Biosciences, Cardiff University, Cardiff, CF10 3AT, Wales, UK

    Colin Berry

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  1. Yasel Guerra
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  2. Pedro A. Valiente
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  3. Colin Berry
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  4. Tirso Pons
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Corresponding authors

Correspondence to Yasel Guerra or Tirso Pons.

Electronic supplementary material

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Table 1

Quality parameters SLAPI 3D models and templates (PDF 97 kb)

Fig. 1

Principal component analysis of the 3D models of SLAPI. (a) Eigenvalues, in decreasing order of magnitude obtained from the backbone coordinates covariance matrix of the chosen models. (b) Root mean square fluctuation (rmsf) per atom in the PC1 (Up panel) and PC2 (Bottom panel) modes. The dashed black oval enclosed loop L9 region of the SLAPI models. (c) Projection of the 3D models of SLAPI onto the subspace spanned by PC1 and PC2. The dashed black oval enclosed the SLAPI models built using the 3D structure 3iir as template. (PDF 97 kb)

Table 2

Protein-protein interface residues predicted by meta-PPISP web server (PDF 604 kb)

Table 3

Residues forming pockets in the proteinase A crystal structure (PDF 109 kb)

Table 4

Frequency of appearance of SLAPI contact residues (PDF 350 kb)

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Guerra, Y., Valiente, P.A., Berry, C. et al. Predicting functional residues of the Solanum lycopersicum aspartic protease inhibitor (SLAPI) by combining sequence and structural analysis with molecular docking. J Mol Model 18, 2673–2687 (2012). https://doi.org/10.1007/s00894-011-1290-2

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