Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus
Crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus
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DOI：
10.1073/pnas.96.23.13034
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发表时间：
1999-11-09
影响因子：
11.1
通讯作者：
Rey, FA
中科院分区：
文献类型：
--
作者：
Bressanelli, S;Tomei, L;Rey, FA
我们报道了一种主要的人类病原体丙型肝炎病毒的RNA依赖RNA聚合酶的晶体结构，分辨率为2.8埃。这种酶是开发特异性抗病毒治疗的关键靶点。催化结构域的结构包含531个残基，折叠在特征手指，手掌和拇指子结构域中。手指子结构域包含一个区域，“指尖”，与逆转录酶共享相同的折叠。与后者的可用结构叠加表明，手掌和指尖的残留物在结构上是等效的。此外，它表明丙型肝炎病毒聚合酶结晶为一个闭合的手指构象，类似于HIV-1逆转录酶与DNA和dTTP的三联物[Huang H., Chopra， R., Verdine， G. L. & Harrison， S. C. (1998) Science 282, 1669-1675]。这种叠加揭示了丙型肝炎病毒酶的大多数氨基酸残基可能与与复制RNA分子和传入NTP的结合有关。这也表明了拇指结构域的重排，以及在RNA模板引物在连续聚合回合的易位过程中拇指和指尖可能的协调运动。
We report the crystal structure of the RNA-dependent RNA polymerase of hepatitis C virus, a major human pathogen, to 2.8-Angstrom resolution. This enzyme is a key target for developing specific antiviral therapy. The structure of the catalytic domain contains 531 residues folded in the characteristic fingers, palm, and thumb subdomains. The fingers subdomain contains a region, the "fingertips," that shares the same fold with reverse transcriptases. Superposition to the available structures of the latter shows that residues from the palm and fingertips are structurally equivalent. In addition, it shows that the hepatitis C virus polymerase was crystallized in a closed fingers conformation, similar to HIV-1 reverse transcriptase in ternary complex with DNA and dTTP [Huang H., Chopra, R., Verdine, G. L. & Harrison, S. C. (1998) Science 282, 1669-1675]. This superposition reveals the majority of the amino acid residues of the hepatitis C virus enzyme that are likely to be implicated in binding to the replicating RNA molecule and to the incoming NTP. It also suggests a rearrangement of the thumb domain as well as a possible concerted movement of thumb and fingertips during translocation of the RNA template-primer in successive polymerization rounds.