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J. Biol. Chem., Vol. 281, Issue 16, 11366-11373, April 21, 2006

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The Structure of CodY, a GTP- and Isoleucine-responsive Regulator of Stationary Phase and Virulence in Gram-positive Bacteria^*

Vladimir M. Levdikov, Elena Blagova, Pascale Joseph¹, Abraham L. Sonenshein, and Anthony J. Wilkinson²

From the Structural Biology Laboratory, Department of Chemistry, University of York, York YO10 5YW, United Kingdom and the Department of Molecular Biology and Microbiology, Tufts University School of Medicine, Boston, Massachusetts 02111

CodY is a global regulator of transcription in Gram-positive bacteria. It represses during growth genes required for adaptation to nutrient limitation, including virulence genes in some human pathogens. CodY activity is regulated by GTP and branched chain amino acids, metabolites whose intracellular concentrations drop as cells enter stationary phase. Although CodY has a highly conserved sequence, it has no significant similarity to proteins of known structure. Here we report crystal structures of two fragments of CodY from Bacillus subtilis that clearly constitute its cofactor and DNA binding domains and reveal that CodY is a chimera of previously observed folding units. The N-terminal cofactor-binding fragment adopts a fold reminiscent of the GAF domains found in cyclic nucleotide phosphodiesterases and adenylate cyclases. It is a dimer stabilized by an intermolecular six -helical bundle that buries an extensive apolar surface rich in residues invariant in CodY orthologues. The branched chain amino acid ligands reside in hydrophobic pockets of each monomer distal to the dimer-forming surface. The structure of the C-terminal DNA binding domain belongs to the winged helix-turn-helix family. The implications of the structure for DNA binding by CodY and its control by cofactor binding are discussed.

Received for publication, December 6, 2005 , and in revised form, January 20, 2006.

The atomic coordinates and structure factors (codes 2B18 (CodY-(1-155)) and 2BOL (CodY-(168-259))) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* This work was supported by the Biotechnology and Biological Science Research Council, United Kingdom, Grant BBS/B/1213X, European Union SPINE Contract QLG2-CT-2002-00988, and United States Public Health Service Grant GM042219. 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.

¹ Present address: Laboratoire de Microbiologie et Pathologie Cellulaire Infectieuse, INSERM U431, Universite de Montpellier II, Place E. Bataillon, 34095 Montpellier, France.

² To whom correspondence should be addressed. Tel.: 44-1904-328261; Fax: 44-1904-328366; E-mail: ajw{at}ysbl.york.ac.uk.

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