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J. Biol. Chem., Vol. 283, Issue 16, 10872-10880, April 18, 2008

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Allosteric Motions in Structures of Yeast NAD⁺-specific Isocitrate Dehydrogenase^*

Alexander B. Taylor¹, Gang Hu¹², P. John Hart^¶3, and Lee McAlister-Henn⁴

From the Department of Biochemistry and X-ray Crystallography Core Laboratory, The University of Texas Health Science Center, San Antonio, Texas 78229 and the ^¶Geriatric Research, Education, and Clinical Center, Department of Veterans Affairs, South Texas Veterans Health Care System, San Antonio, Texas 78229

Mitochondrial NAD⁺-specific isocitrate dehydrogenases (IDHs) are key regulators of flux through biosynthetic and oxidative pathways in response to cellular energy levels. Here we present the first structures of a eukaryotic member of this enzyme family, the allosteric, hetero-octameric, NAD⁺-specific IDH from yeast in three forms: 1) without ligands, 2) with bound analog citrate, and 3) with bound citrate + AMP. The structures reveal the molecular basis for ligand binding to homologous but distinct regulatory and catalytic sites positioned at the interfaces between IDH1 and IDH2 subunits and define pathways of communication between heterodimers and heterotetramers in the hetero-octamer. Disulfide bonds observed at the heterotetrameric interfaces in the unliganded IDH hetero-octamer are reduced in the ligand-bound forms, suggesting a redox regulatory mechanism that may be analogous to the "on-off" regulation of non-allosteric bacterial IDHs via phosphorylation. The results strongly suggest that eukaryotic IDH enzymes are exquisitely tuned to ensure that allosteric activation occurs only when concentrations of isocitrate are elevated.

Received for publication, October 22, 2007 , and in revised form, January 22, 2008.

The atomic coordinates and structure factors (codes 3BLX, 3BLV, and 3BLW) 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 National Institutes of Health Grant 5R01GM051265 (to L. M.-H.) and Robert A. Welch Foundation Grant AQ-1399 (to P. J. H.). 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 on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1-7.

¹ These authors contributed equally to this work.

² Current address: Dept. of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801.

³ To whom correspondence may be addressed. Tel.: 210-567-0751; Fax: 210-567-6595; E-mail: pjhart{at}biochem.uthscsa.edu.

⁴ To whom correspondence may be addressed. Tel.: 210-567-3782; Fax: 210-567-6595; E-mail: henn{at}uthscsa.edu.

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