Bencharit Sompop, Morton Christopher L, Xue Yu, Potter Philip M, Redinbo Matthew R
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, USA.
Nat Struct Biol. 2003 May;10(5):349-56. doi: 10.1038/nsb919.
We present the first crystal structures of a human protein bound to analogs of cocaine and heroin. Human carboxylesterase 1 (hCE1) is a broad-spectrum bioscavenger that catalyzes the hydrolysis of heroin and cocaine, and the detoxification of organophosphate chemical weapons, such as sarin, soman and tabun. Crystal structures of the hCE1 glycoprotein in complex with the cocaine analog homatropine and the heroin analog naloxone provide explicit details about narcotic metabolism in humans. The hCE1 active site contains both specific and promiscuous compartments, which enable the enzyme to act on structurally distinct chemicals. A selective surface ligand-binding site regulates the trimer-hexamer equilibrium of hCE1 and allows each hCE1 monomer to bind two narcotic molecules simultaneously. The bioscavenger properties of hCE1 can likely be used to treat both narcotic overdose and chemical weapon exposure.
我们展示了与可卡因和海洛因类似物结合的人类蛋白质的首个晶体结构。人类羧酸酯酶1（hCE1）是一种广谱生物清除剂，可催化海洛因和可卡因的水解，并对沙林、梭曼和塔崩等有机磷化学武器进行解毒。hCE1糖蛋白与可卡因类似物后马托品和海洛因类似物纳洛酮形成复合物的晶体结构，为人类的麻醉品代谢提供了明确的细节。hCE1活性位点包含特定和混杂的区域，这使得该酶能够作用于结构不同的化学物质。一个选择性表面配体结合位点调节hCE1的三聚体-六聚体平衡，并允许每个hCE1单体同时结合两个麻醉品分子。hCE1的生物清除特性可能可用于治疗麻醉品过量中毒和化学武器暴露。
