Abuhammad Areej, Lowe Edward D, McDonough Michael A, Shaw Stewart Patrick D, Kolek Stefan A, Sim Edith, Garman Elspeth F
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, England.
Acta Crystallogr D Biol Crystallogr. 2013 Aug;69(Pt 8):1433-46. doi: 10.1107/S0907444913015126. Epub 2013 Jul 17.
Arylamine N-acetyltransferase from Mycobacterium tuberculosis (TBNAT) plays an important role in the intracellular survival of the microorganism inside macrophages. Medicinal chemistry efforts to optimize inhibitors of the TBNAT enzyme have been hampered by the lack of a three-dimensional structure of the enzyme. In this paper, the first structure of TBNAT, determined using a lone crystal produced using cross-seeding with the homologous protein from M. marinum, is reported. Despite the similarity between the two enzymes (74% sequence identity), they show distinct physical and biochemical characteristics. The structure elegantly reveals the characteristic features of the protein surface as well as details of the active site of TBNAT relevant to drug-discovery efforts. The crystallographic analysis of the diffraction data presented many challenges, since the crystal was twinned and the habit possessed pseudo-translational symmetry.
结核分枝杆菌芳胺 N - 乙酰基转移酶（TBNAT）在巨噬细胞内微生物的细胞内存活中起重要作用。由于缺乏该酶的三维结构，优化 TBNAT 酶抑制剂的药物化学研究受到阻碍。本文报道了通过与海分枝杆菌同源蛋白交叉接种产生的单晶体确定的 TBNAT 的首个结构。尽管这两种酶之间存在相似性（序列同一性为 74%），但它们表现出不同的物理和生化特性。该结构巧妙地揭示了蛋白质表面的特征以及与药物发现工作相关的 TBNAT 活性位点的细节。由于晶体存在孪晶且晶习具有伪平移对称性，对衍射数据的晶体学分析面临诸多挑战。
