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J. Biol. Chem., Vol. 283, Issue 23, 16216-16225, June 6, 2008

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The Structural Basis for Allosteric Inhibition of a Threonine-sensitive Aspartokinase^*

From the Department of Chemistry, University of Toledo, Toledo, Ohio 43606

The commitment step to the aspartate pathway of amino acid biosynthesis is the phosphorylation of aspartic acid catalyzed by aspartokinase (AK). Most microorganisms and plants have multiple forms of this enzyme, and many of these isofunctional enzymes are subject to feedback regulation by the end products of the pathway. However, the archeal species Methanococcus jannaschii has only a single, monofunctional form of AK. The substrate L-aspartate binds to this recombinant enzyme in two different orientations, providing the first structural evidence supporting the relaxed regiospecificity previously observed with several alternative substrates of Escherichia coli AK ( Angeles, T. S., Hunsley, J. R., and Viola, R. E. (1992) Biochemistry 31, 799-805[CrossRef][Medline] [Order article via Infotrieve] ). Binding of the nucleotide substrate triggers significant domain movements that result in a more compact quaternary structure. In contrast, the highly cooperative binding of the allosteric regulator L-threonine to multiple sites on this dimer of dimers leads to an open enzyme structure. A comparison of these structures supports a mechanism for allosteric regulation in which the domain movements induced by threonine binding causes displacement of the substrates from the enzyme, resulting in a relaxed, inactive conformation.

Received for publication, January 29, 2008 , and in revised form, March 6, 2008.

The atomic coordinates and structure factors (codes 3C20, 3C1N, and 3C1M) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

^* 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 To whom correspondence should be addressed: Dept. of Chemistry, University of Toledo, 2801 W. Bancroft St., Toledo, OH 43606. Tel.: 419-530-1582; Fax: 419-530-1583; E-mail: ron.viola{at}utoledo.edu.

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