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J. Biol. Chem., Vol. 283, Issue 33, 22347-22351, August 15, 2008

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Crystal Structure of the Lysine Riboswitch Regulatory mRNA Element^*

Andrew D. Garst, Annie Héroux, Robert P. Rambo^¶, and Robert T. Batey¹

From the Department of Chemistry and Biochemistry, University of Colorado, Boulder, Boulder, Colorado 80309, the Biology Department, Brookhaven National Laboratory, Upton, New York 11973, and the ^¶Life Science Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720

Riboswitches are metabolite-sensitive elements found in mRNAs that control gene expression through a regulatory secondary structural switch. Along with regulation of lysine biosynthetic genes, mutations within the lysine-responsive riboswitch (L-box) play a role in the acquisition of resistance to antimicrobial lysine analogs. To understand the structural basis for lysine binding, we have determined the 2.8Å resolution crystal structure of lysine bound to the Thermotoga maritima asd lysine riboswitch ligand-binding domain. The structure reveals a complex architecture scaffolding a binding pocket completely enveloping lysine. Mutations conferring antimicrobial resistance cluster around this site as well as highly conserved long range interactions, indicating that they disrupt lysine binding or proper folding of the RNA. Comparison of the free and bound forms by x-ray crystallography, small angle x-ray scattering, and chemical probing reveals almost identical structures, indicating that lysine induces only limited and local conformational changes upon binding.

Received for publication, June 12, 2008

^* This work was supported, in whole or in part, by National Institutes of Health Grant GM073850 (to R. T. B.). R. T. B. is a paid consultant of BioRelix, a company dedicated to developing antibiotic therapeutics targeted against riboswitches. 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 3D0U, 3D0X) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

The on-line version of this article (available at http://www.jbc.org) contains two supplemental tables and six supplemental figures.

¹ To whom correspondence should be addressed: Dept. of Chemistry and Biochemistry, University of Colorado-Boulder, Campus Box 215, Boulder, CO 80309-0215. Tel.: 303-735-2159; Fax: 303-492-5894; E-mail: robert.batey{at}colorado.edu.

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