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

DOPA decarboxylase (DDC) is responsible for the synthesis of the key neurot ransmitters dopamine and serotonin via decarboxylation of L-3,4-dihydroxyph enylalanine (L-DOPA) and L-5-hydroxy-tryptophan, 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 it s complex with the anti-Parkinson drug carbiDOPA. The inhibitor is bound to the enzyme by forming a hydrazone linkage with the cofactor, and its catec hol ring is deeply buried in the active site cleft. The structures provide the molecular basis for the development of new inhibitors of DDC with bette r pharmacological characteristics.