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J. Biol. Chem., Vol. 279, Issue 15, 15491-15498, April 9, 2004

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Crystal Structure of Imidazole Glycerol-phosphate Dehydratase

DUPLICATION OF AN UNUSUAL FOLD^*

Sangita C. Sinha, Barnali N. Chaudhuri¶, John W. Burgner, Galina Yakovleva||, V. Jo Davisson||, and Janet L. Smith**

From the Department of Biological Sciences and the ^||Department of Medicinal Chemistry and Pharmacology, Purdue University, West Lafayette, Indiana 47907

Imidazole glycerol-phosphate dehydratase (IGPD) catalyzes the sixth step of histidine biosynthesis. The enzyme is of fundamental biochemical interest, because it catalyzes removal of a non-acidic hydrogen atom in the dehydration reaction. It is also a potential target for development of herbicides. IGPD is a metalloenzyme in which transition metals induce aggregation and are required for catalysis. Addition of 1 equivalent of Mn²⁺/subunit is shown by analytical ultracentrifugation to induce the formation of 24-mers from trimeric IGPD. Two histidine-rich motifs may participate in metal binding and aggregation. The 2.3-Å crystal structure of metal-free trimeric IGPD from the fungus Filobasidiella neoformans reveals a novel fold containing an internal repeat, apparently the result of gene duplication. The 95-residue / half-domain occurs in a few other proteins, including the GHMP kinase superfamily (galacto-homoserine-mevalonate-phosphomevalonate), but duplication to form a compact domain has not been seen elsewhere. Conserved residues cluster at two types of sites in the trimer, each site containing a conserved histidine-rich motif. A model is proposed for the intact, active 24-mer in which all highly conserved residues, including the histidine-rich motifs in both the N- and C-terminal halves of the polypeptide, cluster at a common site between trimers. This site is a candidate for the active site and also for metal binding leading to aggregation of trimers. The structure provides a basis for further studies of enzyme function and mechanism and for development of more potent and specific herbicides.

Received for publication, November 20, 2003 , and in revised form, January 13, 2004.

The atomic coordinates and structure factors (code 1RHY) 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 Grants GM-45756 (to V. J. D.) and DK-42303 (to J. L. S.). 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.

Current address: Howard Hughes Medical Institute, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390.

^¶ Current address: UCLA-DOE Laboratory of Structural Biology and Molecular Medicine, Box 951570, UCLA, 611 Charles Young Dr., Los Angeles, CA 90095-1570.

^** To whom correspondence should be addressed. Tel.: 765-494-9246; Fax: 765-496-1189; E-mail: smithj{at}purdue.edu.

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