随着近年来禽流感在世界各地的不时出现，令世人闻其色变，找到H5N1禽流感病毒的“死穴”已成为科学家们的愿望。由华人女科学家Yizhi Jane Tao（陶怡芝）和Qiaozhen Ye （叶巧真）领导的一个小组，就找到了H5N1病毒的弱点，那就是促使它长形的蛋白尾巴发生突变，来阻止病毒感染其它细胞。这个办法推而广之，或可有效遏制其它流感的传播。他们在星期四的Nature上报道了这一发现。
　　这个潜在的靶向位点是就是H5N1病毒长形蛋白尾巴的环形部分。这种称为核蛋白的物质，主要用途是“挟持”并潜入宿主细胞，使之成为病毒制造工厂。 其对于病毒的复制具有重要作用. 核蛋白凝聚成一个个小环状，层层重叠成一条圆柱。病毒的核糖核酸染色体组会围绕这条圆柱，然后复制病毒再侵袭其它细胞，可见核蛋白是传播病毒的“元凶”。专家由此发现只要令这个核蛋白圈氨基酸产生突变，便足以阻止核蛋白形成圆柱状，从而阻碍病毒的扩散。
　　研究人员相信病毒尾部的环状部位是其弱点，仅仅是环状部位的氨基酸位置上的一个单突变，便足以干扰其装配。先前的遗传学研究表明，尾部上的环状结构是甲型流感病毒的共有特征，所以针对这个靶点的药物将有很大的可能对包括H5N1在内的多种毒株有效，这为新的抗病毒药物的研究提供了可能。

原文出处：
The mechanism by which influenza A virus nucleoprotein forms oligomers and binds RNA
Qiaozhen Ye, Robert M. Krug and Yizhi Jane Tao
doi:10.1038/nature05379
First paragraph | Full Text | PDF (905K) | Supplementary information

作者简介：
Yizhi Tao
Assistant Professor in Biochemistry and Cell Biology
Rice University ，Department of Biochemistry and Cell Biology
  B.S. Biology (1992) Peking University
  Ph.D. Biological Sciences (1999) Purdue University
  Structural Biology; Virology; Influenza viruses; Birnaviruses
  Center for Biological and Environmental Nanotechnology
  Institute of Biosciences and Bioengineering

All RNA viruses encode an RNA-dependent RNA polymerase, which catalyzes both replication and transcription of the viral genome. We are interested how RNA viruses (e.g. birnaviruses and influenza viruses) exert regulation over RNA synthesis through polymerase interactions with host and cellular factors. We tackle problems in these areas with biochemical means, electron microscopy, and X-ray crystallography. Results from our studies are likely to uncover potential new targets for antiviral drug design.
(a) Birnaviruses. Birnaviruses are pathogens of economically important animals such as chicken and fish. Like in many other DNA and RNA viruses, the initiation of RNA synthesis in birnaviruses is dependent on a protein primer. The birnavirus VP1 functions as polymerase as well as viral protein primer. As a naturally occurring genetic fusion protein, VP1 serves as an excellent model system for structural studies of viral protein priming. We have recently determined a VP1 crystal structure, which reveals a distinct active site topology and a novel protein-priming domain. Further functional studies combined with structural studies of VP1:substrate complexes are likely to provide important insights into the structural basis of viral protein priming.
(b) Influenza viruses. Initiation of viral RNA transcription in influenza viruses requires a short, capped RNA primer snatched from host mRNAs. As transcription progresses toward the end of template, viral polymerase stutters at a poly(U) sequence to produce a poly(A) tail. Different from mRNA transcription, replication of viral genome is primer-independent and the polymerase is able to read through the pre-termination signal. Replication and transcription of influenza viral RNA require four viral proteins PA, PB1, PB2, and NP. Our laboratory uses biochemical assays and structural methods to determine how these four proteins mediate two RNA synthesis reactions with different initiation and termination mechanisms.
Publications
Kim, J., Tao, Y., Reinisch, K.M., Harrison, S.C., and Nibert, M.L. "Orthoreovirus and Aquareovirus Cor Proteins: Conserved Enzymatic Surfaces, but not Protein-protein Interfaces."  Virus Res., 101 (2004): 15-28.

Sayes, C.M., Fortner, J.D., Lyon, D., Boyd, A.M., Ausman K.D., Guo W., Tao Y., Sitharaman, B., Wilson, L.J., West, J.L., and Colvin, V.L. "The Differential Cytotoxicity of Water-Soluble Fullerenes."  Nano Letters, 4 (2004): 1881-1887.

Allison. S.L., Tao, Y.J., O'Riordain, G., Mandl, C.W., Harrison, S.C., and Heinz, F.X. "Two distinct size classes of immature and mature subviral particles from tick-borne encephalitis virus."  Journal of Virology, 77 (2003): 11357-11366.

Tao, Y., Farsetta, D.L., Nibert, M.L., and Harrison, S.C. "RNA Synthesis in a Cage -- Structural Studies on Reovirus Polymerase lambda-3."  Cell, 111 (2002): 733-745.

Morais, M.C., Tao, Y., Olson, N.H., Grimes, S., Jardine, P.J., Anderson, D.L., Baker, T.S., and Rossmann, M.G. "Cryo-EM Image Reconstruction of Symmetry Mismatch in Bacteriophage f29."  J. Struct. Biol., 135 (2001): 38-46.

Simpson, A.A., Leiman, P.G., Tao, Y., He, Y., Badasso, M.O., Jardine, P.J., Anderson, D.L, and Rossmann, M.G. "Crystal Structure Determination of the Head-Tail Connector of Bacteriophage f29."  Acta Crystallogr. D Biol. Crystallogr., 57 (2001): 1260-1269.

Badasso, M.O., Leiman, P.G., Tao, Y., He, Y., Ohlendorf, D.H., Rossmann, M.G., and Anderson, D., "Purification, Crystallization and Initial X-ray Analysis of the Head-Tail Connector of Bacteriophage phi29."  Acta Crystallog. D Biol. Crystallog., 56 (2000): 1187-1190.

Tao, Y., and Zhang, W. "Review: Recent Developments in Cryoelectron Microscopy Reconstructing of Single Particles."  Curr. Opin. Struct. Biol., 10 (2000): 616-622.

Simpson, A.A., Tao, Y. (Equal contributors), Leiman, P.G., Badasso, M.O., He, Y ., Jardine, P.J., Olson, N.H., Morais, M.C., Grimes, S., Anderson, D.L., Baker, T.S., and Rossmann, M.G. "Structure of the Bacteriophage phi29 DNA Packaging Motor."  Nature, 408 (2000): 745-750.

Rossmann, G.M., and Tao, Y. "Cryo-electron-microscopy Reconstruction of Partially Symmetric Objects."  J. Struct. Biol., 125 (1999): 196-208.

Rossmann, M.G., and Tao, Y. "Review: Courageous Science: Structural Studies of Bluetongue Virus Core."  Structure Fold Des., 7 (1999): R43-46.

Rossmann, M.G., and Tao, Y. "Review: Structural Insight into Insect Viruses."  Nat. Struct. Biol., 6 (1999): 717-719.

Tao, Y., Olson, N.H., Xu, W., Anderson, D.L., Rossmann, M.G., and Baker, T.S., "Assembly of a Tailed Bacterial Virus and its Genome Release Studied in Three Dimensions."  Cell, 95 (1998): 431-437.

Qiaozhen Ye
Postdoctoral fellow
Root: Ph.D. Zhongshan (Sun-Yat-Sen) U. 1999; M.S. Zhongshan U. 1993; B.Sc.
Zhongshan U. 1987

　　　　　　　　　　　　　　　　　　　　　　　　　摘自《生物谷》