Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase
Structural insight into Parkinson's disease treatment from drug-inhibited DOPA decarboxylase
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DOI：
10.1038/nsb1101-963
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发表时间：
2001-11-01
期刊：
影响因子：
--
通讯作者：
Malashkevich, VN
中科院分区：
文献类型：
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作者：
Burkhard, P;Dominici, P;Malashkevich, VN
多巴脱羧酶（DDC）负责通过L-3，4-二羟基苯丙氨酸（L-DOPA）和L-5-羟基色氨酸的脱羧分别合成关键的神经递质多巴胺和5-羟色胺。DDC与许多临床疾病有关，包括帕金森病和高血压。DDC的外周抑制剂目前用于治疗这些疾病。我们提出了无配体DDC及其与抗帕金森病药物carbiDOPA的复合物的晶体结构。抑制剂通过与辅因子形成腙键与酶结合，并且其儿茶酚环深埋在活性位点裂缝中。这些结构为开发具有更好药理学特性的DDC抑制剂提供了分子基础。
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-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 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.