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J. Biol. Chem., Vol. 281, Issue 3, 1573-1579, January 20, 2006

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Molecular Architecture and Ligand Recognition Determinants for T4 RNA Ligase^*

Kamel El Omari, Jingshan Ren, Louise E. Bird, Marion K. Bona, George Klarmann¶, Stuart F. J. LeGrice¶, and David K. Stammers1

From the Division of Structural Biology, The Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford, OX3 7BN, UK, Science Applications International Company, Frederick, Maryland 21702, and ^¶HIV Drug Resistance Program, NCI-Frederick, National Institutes of Health, Frederick, Maryland 21702-1201

RNA ligase type 1 from bacteriophage T4 (Rnl1) is involved in countering a host defense mechanism by repairing 5'-PO₄ and 3'-OH groups in tRNA^Lys. Rnl1 is widely used as a reagent in molecular biology. Although many structures for DNA ligases are available, only fragments of RNA ligases such as Rnl2 are known. We report the first crystal structure of a complete RNA ligase, Rnl1, in complex with adenosine 5'-(,-methylenetriphosphate) (AMPcPP). The N-terminal domain is related to the equivalent region of DNA ligases and Rnl2 and binds AMPcPP but with further interactions from the additional N-terminal 70 amino acids in Rnl1 (via Tyr³⁷ and Arg⁵⁴) and the C-terminal domain (Gly²⁶⁹ and Asp²⁷²). The active site contains two metal ions, consistent with the two-magnesium ion catalytic mechanism. The C-terminal domain represents a new all -helical fold and has a charge distribution and architecture for helix-nucleic acid groove interaction compatible with tRNA binding.

Received for publication, September 1, 2005 , and in revised form, October 19, 2005.

^* This work was funded by Federal funds from NCI, National Institutes of Health, under Contract N01-CO-12400 (Article H.36 of the Prime Contract). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The atomic coordinates and structure factors (code 2C5U) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

¹ To whom correspondence should be addressed. Tel.: 44-1865-287565; Fax: 44-1865-287547; E-mail: daves{at}strubi.ox.ac.uk.

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