Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid
Structure and mechanism of inosine monophosphate dehydrogenase in complex with the immunosuppressant mycophenolic acid
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DOI：
10.1016/s0092-8674(00)81275-1
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发表时间：
1996-06-14
期刊：
影响因子：
64.5
通讯作者：
Wilson, KP
中科院分区：
文献类型：
--
作者：
Sintchak, MD;Fleming, MA;Wilson, KP
用X-射线衍射法测定了肌苷-5 '-单磷酸脱氢酶（IMPDH）与IMP和霉酚酸（MPA）复合物的结构。IMPDH在B和T淋巴细胞复制中起中心作用。MPA是一种有效的IMPDH抑制剂，也是最近批准用于治疗同种异体移植排斥反应的免疫抑制药物的活性代谢产物。IMPDH包含两个结构域：核心结构域和侧翼结构域，核心结构域是α/β桶并含有活性位点。复合物，结合诱变和动力学数据，提供了一个结构基础，了解IMPDH活性的机制，并表明MPA抑制IMPDH作为替代的烟酰胺腺嘌呤二核苷酸辅因子和催化水分子的烟酰胺部分。
The structure of inosine-5'-monophosphate dehydrogenase (IMPDH) in complex with IMP and mycophenolic acid (MPA) has been determined by X-ray diffraction. IMPDH plays a central role in B and T lymphocyte replication. MPA is a potent IMPDH inhibitor and the active metabolite of an immunosuppressive drug recently approved for the treatment of allograft rejection. IMPDH comprises two domains: a core domain, which is an alpha/beta barrel and contains the active site, and a flanking domain. The complex, in combination with mutagenesis and kinetic data, provides a structural basis for understanding the mechanism of IMPDH activity and indicates that MPA inhibits IMPDH by acting as a replacement for the nicotinamide portion of the nicotinamide adenine dinucleotide cofactor and a catalytic water molecule.