Filgueira de Azevedo Walter, Canduri Fernanda, Marangoni dos Santos Denis, Pereira José Henrique, Dias Márcio Vinicius Bertacine, Silva Rafael Guimarães, Mendes Maria Anita, Basso Luiz Augusto, Palma Mário Sérgio, Santos Diógenes Santiago
Departamento de Física, UNESP, São José do Rio Preto, SP 15054-000, Brazil.
Biochem Biophys Res Commun. 2003 Oct 3;309(4):917-22. doi: 10.1016/j.bbrc.2003.08.094.
Purine nucleoside phosphorylase (PNP) catalyzes the phosphorolysis of the N-ribosidic bonds of purine nucleosides and deoxynucleosides. PNP is a target for inhibitor development aiming at T-cell immune response modulation. This work reports on the crystallographic study of the complex of human PNP-immucillin-H (HsPNP-ImmH) solved at 2.6A resolution using synchrotron radiation. Immucillin-H (ImmH) inhibits the growth of malignant T-cell lines in the presence of deoxyguanosine without affecting non-T-cell tumor lines. ImmH inhibits activated normal human T cells after antigenic stimulation in vitro. These biological effects of ImmH suggest that this agent may have utility in the treatment of certain human diseases characterized by abnormal T-cell growth or activation. This is the first structural report of human PNP complexed with immucillin-H. The comparison of the complex HsPNP-ImmH with recent crystallographic structures of human PNP explains the high specificity of immucillin-H for human PNP.
嘌呤核苷磷酸化酶（PNP）催化嘌呤核苷和脱氧核苷的N-核糖苷键的磷酸解。PNP是旨在调节T细胞免疫反应的抑制剂开发的靶点。这项工作报道了使用同步辐射以2.6埃分辨率解析的人PNP-免疫菌素-H（HsPNP-ImmH）复合物的晶体学研究。免疫菌素-H（ImmH）在脱氧鸟苷存在的情况下抑制恶性T细胞系的生长，而不影响非T细胞肿瘤系。ImmH在体外抗原刺激后抑制活化的正常人T细胞。ImmH的这些生物学效应表明，该药物可能在治疗某些以T细胞生长或活化异常为特征的人类疾病中具有应用价值。这是关于人PNP与免疫菌素-H复合的首次结构报告。HsPNP-ImmH复合物与最近的人PNP晶体结构的比较解释了免疫菌素-H对人PNP的高特异性。
