Somoza J R, Chin M S, Focia P J, Wang C C, Fletterick R J
Department of Biochemistry and Biophysics, University of California, San Francisco 94143-0448, USA.
Biochemistry. 1996 Jun 4;35(22):7032-40. doi: 10.1021/bi953072p.
The crystal structure of the hypoxanthine-guanine-xanthine phosphoribosyltransferase (HGXPRTase) from Tritrichomonas foetus has been determined and refined against X-ray data to 1.9 A resolution. T. foetus HGXPRTase crystallizes as an asymmetric dimer, with GMP bound to only one of the two molecules that form the asymmetric unit. Each molecule of HGXPRTase is formed by two lobes joined by a short "hinge" region, and the GMP binds in a cavity between the two lobes. A comparison of the two molecules in the asymmetric unit shows that the hinge region is flexible and that ligand binding affects the relative positions of the two lobes. The binding of GMP brings the two lobes closer together, rotating one lobe by about 5 degrees relative to the other. T. foetus appears to depend on HGXPRTase for its supply of GMP, making this enzyme a target for antiparasite drug design. A comparison of the structures of T. foetus HGXPRTase and human HGPRTase reveals that, while these enzymes retain a similar polypeptide fold, there are substantial differences between the active sites of these two homologs. These differences suggest that it will be possible to find compounds that selectively inhibit the parasite enzyme.
已确定胎儿三毛滴虫次黄嘌呤 - 鸟嘌呤 - 黄嘌呤磷酸核糖转移酶（HGXPRTase）的晶体结构，并根据X射线数据将其精修至1.9埃分辨率。胎儿三毛滴虫HGXPRTase结晶为不对称二聚体，其中GMP仅与构成不对称单元的两个分子之一结合。HGXPRTase的每个分子由通过短“铰链”区域连接的两个叶组成，并且GMP结合在两个叶之间的腔中。不对称单元中两个分子的比较表明，铰链区域是灵活的，并且配体结合会影响两个叶的相对位置。GMP的结合使两个叶靠得更近，其中一个叶相对于另一个叶旋转约5度。胎儿三毛滴虫似乎依赖HGXPRTase来供应GMP，这使得这种酶成为抗寄生虫药物设计的靶点。胎儿三毛滴虫HGXPRTase与人HGPRTase结构的比较表明，虽然这些酶保留了相似的多肽折叠，但这两种同源物的活性位点之间存在实质性差异。这些差异表明有可能找到选择性抑制寄生虫酶的化合物。
