通过三张丙型肝炎病毒(HCV)动力蛋白及其底物的构象快照，美国洛克菲勒大学的研究人员首次提供了HCV NS3解旋酶沿着核酸链单向移动的证据，这项研究或许有助于药物设计者根据这一特点设计出阻断该病毒复制的药物。
研究人员在之前的研究中已经了解到HCV NS3解旋酶的运动需要ATP提供能量支持，而且科学家也获得了NS3的晶体结构。据最近的一项发表于Proceedings of the National Academy of Sciences的研究报告，Charles M. Rice等人研究显示了ATP如何连续地改造DNA和NS3解旋酶之间的联系，并找到在解旋酶移动过程中起关键作用的因素。
据研究人员Gu介绍，当ATP与NS3结合以及ATP发生水解时，NS3和DNA会发生一系列的重要转变，如果在转变过程中，抑制参与该过程中的某些蛋白，那么将会抑制解旋酶的运动并使病毒复制终止。
通过分子快照，研究人员详细描述了NS3如何沿着核酸底物运动的过程。当NS3与核酸相结合时，NS3的形状类似于希腊字母“λ”。在NS3沿核酸底物单向运动的过程中关键的一点是需要一个磷酸基团的参与。（生物谷Bioon.com）
生物谷推荐原始出处：
PNAS December 31, 2009, doi: 10.1073/pnas.0913380107
Three conformational snapshots of the hepatitis C virus NS3 helicase reveal a ratchet translocation mechanism
Meigang Gu1 and Charles M. Rice1
Center for the Study of Hepatitis C, Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065
A virally encoded superfamily-2 (SF2) helicase (NS3h) is essential for the replication of hepatitis C virus, a leading cause of liver disease worldwide. Efforts to elucidate the function of NS3h and to develop inhibitors against it, however, have been hampered by limited understanding of its molecular mechanism. Here we show x-ray crystal structures for a set of NS3h complexes, including ground-state and transition-state ternary complexes captured with ATP mimics (ADP·BeF3 and ). These structures provide, for the first time, three conformational snapshots demonstrating the molecular basis of action for a SF2 helicase. Upon nucleotide binding, overall domain rotation along with structural transitions in motif V and the bound DNA leads to the release of one base from the substrate base-stacking row and the loss of several interactions between NS3h and the 3′ DNA segment. As nucleotide hydrolysis proceeds into the transition state, stretching of a “spring” helix and another overall conformational change couples rearrangement of the (d)NTPase active site to additional hydrogen-bonding between NS3h and DNA. Together with biochemistry, these results demonstrate a “ratchet” mechanism involved in the unidirectional translocation and define the step size of NS3h as one base per nucleotide hydrolysis cycle. These findings suggest feasible strategies for developing specific inhibitors to block the action of this attractive, yet largely unexplored drug target.
