Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents
Molecular basis for the inhibition of human NMPRTase, a novel target for anticancer agents
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DOI：
10.1038/nsmb1105
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发表时间：
2006-07-01
影响因子：
16.8
通讯作者：
Tong, Liang
中科院分区：
文献类型：
--
作者：
Khan, Javed A.;Tao, Xiao;Tong, Liang
烟酰胺磷酸核糖转移酶 (NMPRTase) 在 NAD(+) 生物合成的补救途径中起着至关重要的作用，NMPRTase 的有效抑制剂 FK866 可以降低细胞 NAD(+) 水平并诱导肿瘤细胞凋亡。我们已经以高达 2.1 埃的分辨率确定了人和鼠 NMPRT 酶的晶体结构，无论是单独的还是与反应产物烟酰胺单核苷酸或抑制剂 FK866 的复合物。这些结构表明 Asp219 是 NMPRTase 底物特异性的决定因素，我们的诱变研究证实了这一点。 FK866 结合在 NMPRTase 二聚体界面的通道中，该结合位点的突变可以消除 FK866 的抑制作用。与目前的知识相反，结构表明 FK866 应直接与烟酰胺底物竞争。我们的结构和生化研究为新型抗癌药物的开发提供了起点。
Nicotinamide phosphoribosyltransferase (NMPRTase) has a crucial role in the salvage pathway of NAD(+) biosynthesis, and a potent inhibitor of NMPRTase, FK866, can reduce cellular NAD(+) levels and induce apoptosis in tumors. We have determined the crystal structures at up to 2.1-angstrom resolution of human and murine NMPRTase, alone and in complex with the reaction product nicotinamide mononucleotide or the inhibitor FK866. The structures suggest that Asp219 is a determinant of substrate specificity of NMPRTase, which is confirmed by our mutagenesis studies. FK866 is bound in a tunnel at the interface of the NMPRTase dimer, and mutations in this binding site can abolish the inhibition by FK866. Contrary to current knowledge, the structures show that FK866 should compete directly with the nicotinamide substrate. Our structural and biochemical studies provide a starting point for the development of new anticancer agents.