structure of the RNA-dependent RNA polymerase from bovine viral diarrhea virus establishes the role of GTP in de novo initiation

The bovine viral diarrhea virus (BVDV) RNA-dependent RNA polymerase can initiate RNA replication by a de novo mechanism without a primer. The structure of BVDV polymerase, determined to 2.9-Å resolution, contains a unique N-terminal domain, in addition to the fingers, palm, and thumb domains common...

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Published in:	Proceedings of the National Academy of Sciences - PNAS Vol. 101; no. 13; pp. 4425 - 4430
Main Authors:	Choi, K.H, Groarke, J.M, Young, D.C, Kuhn, R.J, Smith, J.L, Pevear, D.C, Rossmann, M.G
Format:	Journal Article
Language:	English
Published:	United States National Academy of Sciences 30-03-2004 National Acad Sciences
Subjects:	Active sites Amino Acid Sequence Animals Biological Sciences Biophysics Bovine viral diarrhea virus Cattle Crystallography, X-Ray Crystals Diarrhea Diarrhea Viruses, Bovine Viral - enzymology Dimers Enzymes Fingers Guanosine Triphosphate - chemistry Guanosine Triphosphate - metabolism Models, Molecular Molecular Sequence Data Molecules Monomers Protein Conformation Protein Structure, Secondary Proteins Ribonucleic acid RNA RNA Replicase - chemistry RNA Replicase - metabolism Sequence Alignment Sequence Homology, Amino Acid Thumb Viruses
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Summary:	The bovine viral diarrhea virus (BVDV) RNA-dependent RNA polymerase can initiate RNA replication by a de novo mechanism without a primer. The structure of BVDV polymerase, determined to 2.9-Å resolution, contains a unique N-terminal domain, in addition to the fingers, palm, and thumb domains common to other polymerases. The structure of BVDV polymerase complexed with GTP, which is required for de novo (primer-independent) initiation, shows that GTP binds adjacent to the initiation NTP, suggesting that the GTP mimics a vestigal RNA product. Comparison of five monomers in two different crystal forms showed conformational changes in the fingertip region and in the thumb domain that may help to translocate the RNA template and product strands during elongation. The putative binding sites of previously reported BVDV inhibitors are also discussed.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Present address: Novartis Pharmaceuticals, One Health Plaza, Building 435, East Hanover, NJ 07936. Abbreviations: BVDV, bovine viral diarrhea virus; HCV, hepatitis C virus; NTP, nucleotide triphosphate; RdRp, RNA-dependent RNA polymerase; SeMet, selenomethionine; ssRNA, single-stranded RNA. Data deposition: The atomic coordinates have been deposited in the Protein Data Bank, www.pdb.org [PDB ID codes 1S48 (form 1 crystals), 1S4F (form 2 crystals), and 1S49 (form 1 complexed with GTP)]. Contributed by Michael G. Rossmann, January 31, 2004 To whom correspondence should be addressed. E-mail: mgr@indiana.bio.purdue.edu.
ISSN:	0027-8424 1091-6490
DOI:	10.1073/pnas.0400660101