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J. Biol. Chem., Vol. 278, Issue 34, 32107-32114, August 22, 2003

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The Negative Transcriptional Regulator NmrA Discriminates between Oxidized and Reduced Dinucleotides^*

Heather K. Lamb  , Kris Leslie  ¶, Anna L. Dodds , Margaret Nutley ||, Alan Cooper ||, Christopher Johnson , Paul Thompson , David K. Stammers ¶ ** and Alastair R. Hawkins  

From the School of Cell and Molecular Biosciences, Catherine Cookson Building, University of Newcastle upon Tyne, Framlington Place, NE2 4HH, United Kingdom, ^¶Division of Structural Biology, The Henry Wellcome Building for Genomic Medicine, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, United Kingdom, and the ^||Department of Chemistry, University of Glasgow, Glasgow G12 8QQ, Scotland, United Kingdom

NmrA, a transcription repressor involved in the regulation of nitrogen metabolism in Aspergillus nidulans,is a member of the short-chain dehydrogenase reductase superfamily. Isothermal titration calorimetry and differential scanning calorimetry have been used to show NmrA binds NAD⁺ and NADP⁺ with similar affinity (average K_D 65 µM) but has a greatly reduced affinity for NADH and NADPH (average K_D 6.0 mM). The structure of NmrA in a complex with NADP⁺ reveals how repositioning a His-37 side chain allows the different conformations of NAD⁺ and NADP⁺ to be accommodated. Modeling NAD(P)H into NmrA indicated that steric clashes, attenuation of electrostatic interactions, and loss of aromatic ring stacking can explain the differing affinities of NAD(P)⁺/NAD(P)H. The ability of NmrA to discriminate between the oxidized and reduced forms of the dinucleotides may be linked to a possible role in redox sensing. Isothermal titration calorimetry demonstrated that NmrA and a C-terminal fragment of the GATA transcription factor AreA interacted with a 1:1 stoichiometry and an apparent K_D of 0.26 µM. NmrA was unable to bind the nitrogen metabolite repression signaling molecules ammonium or glutamine.

Received for publication, April 18, 2003 , and in revised form, May 14, 2003.

The atomic coordinates and structure factors (code 1PDS) 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 Sciences Research Council and the Wellcome Trust. 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.

Both authors contributed equally to this work.

^** To whom correspondence may be addressed. Tel.: 44-1865-287-565; Fax: 44-1865-287-547; E-mail: daves{at}strubi.ox.ac.uk.

To whom correspondence may be addressed. Tel.: 44-191-2227673; Fax: 44-191-2227424; E-mail: a.r.hawkins{at}ncl.ac.uk.

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