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Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders

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Abstract

Monoamine oxidase B (MAO B) is a mitochondrial outermembrane flavoenzyme that is a well-known target for antidepressant and neuroprotective drugs. We determined the structure of the human enzyme to 3 Å resolution. The enzyme binds to the membrane through a C-terminal transmembrane helix and apolar loops located at various positions in the sequence. The electron density shows that pargyline, an analog of the clinically used MAO B inhibitor, deprenyl, binds covalently to the flavin N5 atom. The active site of MAO B consists of a 420 Å3-hydrophobic substrate cavity interconnected to an entrance cavity of 290 Å3. The recognition site for the substrate amino group is an aromatic cage formed by Tyr 398 and Tyr 435. The structure provides a framework for probing the catalytic mechanism, understanding the differences between the B- and A-monoamine oxidase isoforms and designing specific inhibitors.

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Figure 1: Substrate specificity and catalysis of MAOs.
Figure 2: Stereo view of the experimental electron density map.
Figure 3: Structure of human MAO B.
Figure 4: The substrate binding site of human MAO B.

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Acknowledgements

This work was supported by grants from the National Institute of General Medical Sciences of the NIH, the Consiglio Nazionale delle Ricerche and Agenzia Spaziale Italiana. We thank the staff of the EMBL/DESY and ESRF facilities for help during the data collection. The European Union provided support through the Human Capital Mobility Program to Large Scale Installations Project. We thank A. Coda, B. Curti, M. Rizzi and R. van den Heuvel for helpful discussions.

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Authors and Affiliations

  1. Department of Genetics and Microbiology, University of Pavia, Pavia, Italy

    Claudia Binda & Andrea Mattevi

  2. Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia, USA

    Paige Newton-Vinson, Frantisek Hubálek & Dale E. Edmondson

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  1. Claudia Binda
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  2. Paige Newton-Vinson
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  3. Frantisek Hubálek
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  4. Dale E. Edmondson
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  5. Andrea Mattevi
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Correspondence to Dale E. Edmondson or Andrea Mattevi.

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Binda, C., Newton-Vinson, P., Hubálek, F. et al. Structure of human monoamine oxidase B, a drug target for the treatment of neurological disorders. Nat Struct Mol Biol 9, 22–26 (2002). https://doi.org/10.1038/nsb732

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