title: Crystal structure of imidazole glycerol-phosphate dehydratase: duplication of an unusual fold.
abstract: 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 Mn(2+)/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-A 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 alpha/beta 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.
authors.affiliation: Department of Biological Sciences, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Sangita C
authors.initials: SC
authors.lastname: Sinha
authors.forename: Barnali N
authors.initials: BN
authors.lastname: Chaudhuri
authors.forename: John W
authors.initials: JW
authors.lastname: Burgner
authors.forename: Galina
authors.initials: G
authors.lastname: Yakovleva
authors.forename: V Jo
authors.initials: VJ
authors.lastname: Davisson
authors.forename: Janet L
authors.initials: JL
authors.lastname: Smith
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D001487:Basidiomycota / Q000378:metabolism; D001665:Binding Sites; D002384:Catalysis; D018360:Crystallography, X-Ray; D019281:Dimerization; D006639:Histidine / Q000737:chemistry; D006836:Hydro-Lyases / Q000737:chemistry*; D006859:Hydrogen / Q000737:chemistry; D008274:Magnesium / Q000737:chemistry; D008958:Models, Molecular; D008969:Molecular Sequence Data; D005810:Multigene Family; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D017510:Protein Folding; D020836:Protein Structure, Quaternary; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D014461:Ultracentrifugation
chemical_list: D010455:Peptides; D006639:Histidine; D006859:Hydrogen; D006836:Hydro-Lyases; C021434:imidazoleglycerolphosphate dehydratase; D008274:Magnesium