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Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation

Nature Structural Biology volume 8, pages 131–135 (2001)Cite this article

Abstract

Leukotriene (LT) A4 hydrolase/aminopeptidase (LTA4H) is a bifunctional zinc enzyme that catalyzes the biosynthesis of LTB4, a potent lipid chemoattractant involved in inflammation, immune responses, host defense against infection, and PAF-induced shock. The high resolution crystal structure of LTA4H in complex with the competitive inhibitor bestatin reveals a protein folded into three domains that together create a deep cleft harboring the catalytic Zn2+ site. A bent and narrow pocket, shaped to accommodate the substrate LTA4, constitutes a highly confined binding region that can be targeted in the design of specific anti-inflammatory agents. Moreover, the structure of the catalytic domain is very similar to that of thermolysin and provides detailed insight into mechanisms of catalysis, in particular the chemical strategy for the unique epoxide hydrolase reaction that generates LTB4.

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Figure 1: Overall and domain structure of LTA4H.
Figure 2: Bestatin binding in LTA4H.
Figure 3: The putative LTA4 binding cavity.
Figure 4: Proposed reaction mechanism for the epoxide hydrolase activity of LTA4H.

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Acknowledgements

We thank A. Thompson at BM14 and D. Logan for help during data collection and setting up SHARP refinement, M. Andberg for the plasmid pT3-MB4 and E. Ohlsson for technical assistance, as well as A. Wetterholm and B. Samuelsson for helpful discussions and advice. We also would like to thank personnel at beamline X25 of the NSLS, Brookhaven, and I711 of MAX-Lab, Lund, for preliminary data not used in this article. The work was funded by the Swedish Natural Sciences Research Council, the Swedish Medical Research Council, The European Union, and Konung Gustav V:s 80-Årsfond.

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Authors and Affiliations

  1. Department of Biochemistry, University of Stockholm, Arrhenius Laboratories A4, Stockholm, S-106 91, Sweden

    Marjolein M.G.M. Thunnissen & Pär Nordlund

  2. Department of Medical Biochemistry & Biophysics, Karolinska Institutet, Stockholm, S-171 77, Sweden

    Jesper Z. Haeggström

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  1. Marjolein M.G.M. Thunnissen
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Correspondence to Marjolein M.G.M. Thunnissen.

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Thunnissen, M., Nordlund, P. & Haeggström, J. Crystal structure of human leukotriene A4 hydrolase, a bifunctional enzyme in inflammation. Nat Struct Mol Biol 8, 131–135 (2001). https://doi.org/10.1038/84117

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