PURINE NUCLEOSIDE PHOSPHORYLASE: NOVEL CHEMOTHER FOR LYMPHOMA & GRAFT REJECTION

嘌呤核苷磷酸化酶(PNP)催化磷酸化 嘌呤核苷生成游离嘌呤和？-1-核糖磷酸。 人类的一种基因缺陷，导致缺乏PNP，导致 T细胞完全丧失，但没有其他影响。因此，PnP是一种 治疗多个T细胞特异性的极佳靶点 病理包括T细胞淋巴瘤和移植物排斥反应。我们有 最近收集的数据好于2.0E，小腿之间的一个复合体 脾PNP和20 PM过渡态抑制物。精致是 正在进行中，目前揭示了 稳定过渡状态的酶，包括一种 构象重排。此结构表示 迄今已解决的亲和力最高的酶-配体复合体将形成 为今后缓蚀剂的开发和机理研究奠定了基础。

Purine nuceloside phosphorylase (PNP) catalyzes the phosphorolysis of purine nucleosides to yield free purines and ?-1-ribose phosphate. A genetic defect in humans that results in the lack of PNP, results in a complete loss of T-cells, but no other effects. Thus PNP is an excellent target for the therapy of a number of T-cell specific pathologies including T-cell lymphomas and graft rejection. We have recently collected data to better than 2.0E on a complex between calf spleen PNP and a 20 pM transition state-inhibitor. Refinement is underway and currently reveals several of the strategies used by this enzyme to stabilize the transition state, which includes a conformational rearrangement. This structure represents one of the highest affinity enzyme-ligand complexes solved to date and will form the basis for future inhibitor development and mechanistic studies.