Sintchak M D, Fleming M A, Futer O, Raybuck S A, Chambers S P, Caron P R, Murcko M A, Wilson K P
Vertex Pharmaceuticals Incorporated, Cambridge, Massachusetts 02139-4211, USA.
Cell. 1996 Jun 14;85(6):921-30. doi: 10.1016/s0092-8674(00)81275-1.
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.
通过X射线衍射确定了肌苷-5'-单磷酸脱氢酶（IMPDH）与肌苷一磷酸（IMP）和霉酚酸（MPA）复合物的结构。IMPDH在B和T淋巴细胞复制中起核心作用。MPA是一种有效的IMPDH抑制剂，也是最近被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由两个结构域组成：一个核心结构域，它是一个α/β桶状结构，包含活性位点，以及一个侧翼结构域。该复合物与诱变和动力学数据相结合，为理解IMPDH活性机制提供了结构基础，并表明MPA通过作为烟酰胺腺嘌呤二核苷酸辅因子的烟酰胺部分和催化水分子的替代物来抑制IMPDH。
