dos Santos Denis Marangoni, Canduri Fernanda, Pereira José Henrique, Vinicius Bertacine Dias Márcio, Silva Rafael Guimarães, Mendes Maria Anita, Palma Mário Sérgio, Basso Luiz Augusto, de Azevedo Walter Filgueira, Santos Diógenes Santiago
Departamento de Física, UNESP, São José do Rio Preto, SP, Brazil.
Biochem Biophys Res Commun. 2003 Aug 29;308(3):553-9. doi: 10.1016/s0006-291x(03)01433-5.
In human, purine nucleoside phosphorylase (HsPNP) is responsible for degradation of deoxyguanosine and genetic deficiency of this enzyme leads to profound T-cell mediated immunosuppression. PNP is therefore a target for inhibitor development aiming at T-cell immune response modulation and has been submitted to extensive structure-based drug design. This work reports the first crystallographic study of human PNP complexed with acyclovir (HsPNP:Acy). Acyclovir is a potent clinically useful inhibitor of replicant herpes simplex virus that also inhibits human PNP but with a relatively lower inhibitory activity (K(i)=90 microM). Analysis of the structural differences among the HsPNP:Acy complex, PNP apoenzyme, and HsPNP:Immucillin-H provides explanation for inhibitor binding, refines the purine-binding site, and can be used for future inhibitor design.
在人类中，嘌呤核苷磷酸化酶（HsPNP）负责脱氧鸟苷的降解，该酶的基因缺陷会导致严重的T细胞介导的免疫抑制。因此，PNP是旨在调节T细胞免疫反应的抑制剂开发的靶点，并已进行了广泛的基于结构的药物设计。这项工作报道了人类PNP与阿昔洛韦复合（HsPNP:Acy）的首次晶体学研究。阿昔洛韦是一种对复制型单纯疱疹病毒有效的临床有用抑制剂，它也抑制人类PNP，但抑制活性相对较低（K(i)=90微摩尔）。对HsPNP:Acy复合物、PNP脱辅酶和HsPNP:Immucillin-H之间结构差异的分析为抑制剂结合提供了解释，完善了嘌呤结合位点，可用于未来的抑制剂设计。
