Engineered Thermoplasma acidophilum factor F3 mimics human aminopeptidase N (APN) as a target for anticancer drug development.

Jing Su, Qiang Wang, Jinhong Feng, Cong Zhang, Deyu Zhu, Tiandi Wei, Wenfang Xu, Lichuan Gu

Journal: Bioorganic & medicinal chemistry 2011;19(9):2991-6

PMID: 21493078

Full Text on Elsevier Science View on PubMed

Abstract

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.

Address: State Key Laboratory of Microbial Technology, Shandong University, Jinan 250100, China.

DOI: 10.1016/j.bmc.2011.03.028

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MeSH Terms: Amino Acid Sequence, Antineoplastic Agents, Archaeal Proteins, Binding Sites, CD13 Antigens, Catalytic Domain, Computer Simulation, Crystallography, X-Ray, Drug Design, Enzyme Inhibitors, Humans, Kinetics, Molecular Sequence Data, Mutation, Organometallic Compounds, Protein Engineering, Protein Structure, Tertiary, Sequence Alignment, Sequence Homology, Amino Acid, Thermoplasma, Zinc