State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, China.
Bioorg Med Chem. 2011 May 1;19(9):2991-6. doi: 10.1016/j.bmc.2011.03.028. Epub 2011 Mar 21.
Human aminopeptidase N (hAPN) is an appealing objective for the development of anti-cancer agents. The absence of mammalian APN experimental structure negatively impinges upon the progression of structure-based drug design. Tricorn interacting factor F3 (factor F3) from Thermoplasma acidophilum shares 33% sequence identity with hAPN. Engineered factor F3 with two point directed mutations resulted in a protein with an active site identical to hAPN. In the present work, the engineered factor F3 has been co-crystallized with compound D24, a potent APN inhibitor introduced by our lab. Such a holo-form experimental structure helpfully insinuates a more bulky pocket than Bestatin-bound Escherichia coli APN. This evidence discloses that compound D24 targetting the structure of E. coli APN cannot bind to the activity cleft of factor F3 with high affinity. Thus, there is a potential risk of inefficiency to design hAPN targeting drug while using E. coli APN as the target model. We do propose here now that engineered factor F3 can be employed as a reasonable alternative of hAPN for drug design and development.
人氨肽酶 N（hAPN）是开发抗癌药物的有吸引力的目标。哺乳动物 APN 实验结构的缺失对基于结构的药物设计的进展产生了负面影响。嗜酸热原体的三齿相互作用因子 F3（因子 F3）与 hAPN 具有 33%的序列同一性。经过两点定向突变工程化的因子 F3 产生了一个与 hAPN 具有相同活性位点的蛋白质。在本工作中，已经将工程化的因子 F3 与我们实验室引入的强效 APN 抑制剂 D24 共结晶。这种完整形式的实验结构有助于暗示一个比 Bestatin 结合的大肠杆菌 APN 更大的口袋。这一证据表明，针对大肠杆菌 APN 结构的化合物 D24 不能以高亲和力结合到因子 F3 的活性裂缝中。因此，在设计针对 hAPN 的靶向药物时，使用大肠杆菌 APN 作为靶模型存在效率低下的风险。我们现在在这里建议，可以使用工程化的因子 F3 作为 hAPN 的合理替代品，用于药物设计和开发。
