DOPA decarboxylase (DCC) is responsible for the conversion of l-3,4-dihydroxyphenylalanine (l-DOPA) to dopamine. Parkinson's disease involves a progressive loss of dopamine-producing cells in the midbrain, and l-DOPA, given orally, remains the most effective treatment for the symptoms of this disorder. Because l-DOPA is rapidly converted to dopamine in the bloodstream, it is routinely administered with a DCC inhibitor (for example, carbiDOPA), allowing greater amounts of l-DOPA to reach the brain. The treatment of patients with Parkinson's disease could be greatly improved by the design of more effective inhibitors of this enzyme. This prospect seems increasingly likely, as Burkhard et al. report the crystal structures of ligand-free DCC, and its complex with carbiDOPA.

X-ray crystallography can be used to obtain high-resolution, three-dimensional models of the structures of proteins and other macromolecules. X-rays are diffracted by electrons of molecules in the crystallized protein, and this diffraction pattern can be used to calculate an electron density map. A model of the protein, which has a known amino-acid sequence, can then be built to fit the map. Using this method, Burkhard and co-workers obtained structures of ligand-free DCC and the DCC–carbiDOPA complex. Several features of DCC were evident in these models: the overall structure of the protein (an α2-dimer), the way in which the cofactor pyridoxal-5′-phosphate (PLP) is anchored to the enzyme, how the inhibitor binds (by forming a hydrazone linkage with PLP), and which amino-acid residues might be involved in the catalytic activity of DCC. Importantly, on the basis of these structures, the authors were able to suggest ways in which the binding of inhibitors of DCC might be improved.

The decrease in forebrain dopamine levels that follows dopaminergic cell loss in Parkinson's disease leads to muscle tremor, and to difficulty in initiating and sustaining locomotion. Although l-DOPA is effective in treating these symptoms, this therapy is associated with side effects that result, in part, from relatively high concentrations of l-DOPA itself, and from the production of dopamine in the bloodstream. The use of more-potent inhibitors of DCC would allow smaller amounts l-DOPA to be used in alleviating the symptoms of Parkinson's disease; the crystal structures reported by Burkhard et al. offer a way forward in the design of such treatments.