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Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase

Nature Structural Biology volume 8, pages 963–967 (2001)Cite this article

Abstract

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurotransmitters dopamine and serotonin via decarboxylation of l-3,4-dihydroxyphenylalanine (l-DOPA) and l-5-hydroxytryptophan, respectively. DDC has been implicated in a number of clinic disorders, including Parkinson's disease and hypertension. Peripheral inhibitors of DDC are currently used to treat these diseases. We present the crystal structures of ligand-free DDC and its complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catechol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with better pharmacological characteristics.

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Figure 1
Figure 2: Stereo view ribbon diagram of the polypeptide backbone of DDC.
Figure 3: Active site cleft of DDC in complex with carbiDOPA.

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Acknowledgements

Special thanks go to E. De La Fortelle and C. Vonrhein for extremely helpful discussion and to R. Huber, Max-Planck Institut für Biochemie, Martinsried, Germany, for his kind gift of the tantalum cluster.

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Author notes

  1. Paola Dominici

    Present address: Dipartimento Scientifico e Tecnologico, Università degli Studi di Verona, 37134, Verona, Italy

  2. Vladimir N. Malashkevich

    Present address: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, Massachusetts, 02142, USA

Authors and Affiliations

  1. M.E. Müller Institute for Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, CH-4056, Switzerland

    Peter Burkhard

  2. Dipartimento di Scienze Neurologiche e della Visione, Sezione di Chimica Biologica, Università di Verona, Strada Le Grazie, 8, Verona, 37134, Italy

    Paola Dominici & Carla Borri-Voltattorni

  3. Department of Structural Biology, Biozentrum, University of Basel, Klingelbergstrasse 70, Basel, CH-4056, Switzerland

    Johan N. Jansonius & Vladimir N. Malashkevich

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  1. Peter Burkhard
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Correspondence to Peter Burkhard.

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Burkhard, P., Dominici, P., Borri-Voltattorni, C. et al. Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase. Nat Struct Mol Biol 8, 963–967 (2001). https://doi.org/10.1038/nsb1101-963

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