A 1.4 A crystal structure for the hypoxanthine phosphoribosyltransferase of Trypanosoma cruzi.
A 1.4 A crystal structure for the hypoxanthine phosphoribosyltransferase of Trypanosoma cruzi.
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A 1.4 克氏锥虫次黄嘌呤磷酸核糖转移酶的晶体结构。
DOI：
10.1021/bi981052s
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发表时间：
1998
期刊：
影响因子：
--
通讯作者：
Eakin,AE
中科院分区：
文献类型：
--
作者：
Focia,PJ;Craig3rd,SP;Nieves-Alicea,R;Fletterick,RJ;Eakin,AE
将恰加斯病病原克氏锥虫的次黄嘌呤磷酸核糖基转移酶（HPRT）与肌苷类似物Formycin B （FmB）共结晶，确定其结构为1.4 Å分辨率。这是迄今为止报道的磷酸核糖基转移酶（PRT）的最高分辨率结构，晶体的不对称单元包含密切相关的二聚体，几乎相同的亚基。一个活性位点环中的保守的非脯氨酸顺式肽将主链氮暴露于酶活性位点，而相邻的赖氨酸侧链与二聚体的其他亚基相互作用，从而为亚基与其活性位点之间的通信提供了可能的机制。本文首次报道了不变性Ser103−Tyr104二肽的三维坐标。这些是第二个活性位点环中仅有的高度保守的残基，称为长柔性环，预计它会关闭hprt的活性位点以保护不稳定的过渡状态[Eads等人（1994）Cell 78, 325−334]。这种结构在设计/发现HPRT - ofT的有效选择性抑制剂方面迈出了重要的一步。cruzi。
The hypoxanthine phosphoribosyltransferase (HPRT) fromTrypanosoma cruzi, etiologic agent of Chagas' disease, was cocrystallized with the inosine analogue Formycin B (FmB) and the structure determined to 1.4 Å resolution. This is the highest resolution structure yet reported for a phosphoribosyltransferase (PRT), and the asymmetric unit of the crystal contains a dimer of closely associated, nearly identical subunits. A conserved nonproline cis peptide in one active-site loop exposes the main-chain nitrogen to the enzyme active site, while the adjacent lysine side chain interacts with the other subunit of the dimer, thereby providing a possible mechanism for communication between the subunits and their active sites. The three-dimensional coordinates for the invariant Ser103−Tyr104 dipeptide are reported here for the first time. These are the only highly conserved residues in a second active-site loop, termed the long flexible loop, which is predicted to close over the active site of HPRTs to protect a labile transition state [Eads et al. (1994)Cell 78, 325−334]. This structure represents a major step forward in efforts to design/discover potent selective inhibitors of the HPRT ofT. cruzi.