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Journal of Virology, August 2006, p. 7909-7917, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00525-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

New Antiviral Target Revealed by the Hexameric Structure of Mouse Hepatitis Virus Nonstructural Protein nsp15

Xiaoling Xu,1,2,{dagger} Yujia Zhai,1,2,{dagger} Fei Sun,1,2 Zhiyong Lou,1,2 Dan Su,1,2 Yuanyuan Xu,1,2 Rongguang Zhang,2,3 Andrzej Joachimiak,3 Xuejun C. Zhang,2,4 Mark Bartlam,1,2 and Zihe Rao1,2*

"Tsinghua-IBP Joint Research Group for Structural Biology," Tsinghua University, Beijing 100084, China,1 National Laboratory of Biomacromolecules, Institute of Biophysics (IBP), Chinese Academy of Sciences, Beijing 100101, China,2 Biosciences Division, Argonne National Laboratory, Argonne, Illinois 60439,3 Crystallography Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 731044

Received 14 March 2006/ Accepted 2 May 2006

The unique coronavirus transcription/replication machinery comprised of multiple virus-encoded nonstructural proteins (nsp) plays a vital role during initial and intermediate phases of the viral life cycle. The crystal structure of mouse hepatitis virus strain A59 (MHV-A59) nsp15 is reported at 2.15-Å resolution. nsp15 is an XendoU endoribonuclease and is the first one from this family to have its structure unveiled. The MHV-A59 nsp15 monomer structure has a novel protein fold. Two nsp15 trimers form a back-to-back hexamer that is believed to be the functional unit. The structure reveals the catalytic site including the highly conserved residues His262, His277, and Lys317, which is supported by mutagenesis analysis. Gel filtration and enzyme activity assays confirmed that the hexamer is the active form for nsp15 and demonstrate the specificity of nsp15 for uridylate. The high sequence conservation of nsp15 in coronaviruses, including that of severe acute respiratory syndrome, suggests that this protein may provide a new target for the design of antiviral therapeutics.

* Corresponding author. Mailing address: Laboratory of Structural Biology, Life Sciences Building, Tsinghua University, Beijing 100084, China. Phone: 86 10 62771493. Fax: 86 10 62773145. E-mail: raozh{at}xtal.tsinghua.edu.cn.

{dagger} These authors made equal contributions.

Journal of Virology, August 2006, p. 7909-7917, Vol. 80, No. 16
0022-538X/06/$08.00+0     doi:10.1128/JVI.00525-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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