title: Structures of native, substrate-bound and inhibited forms of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase.
abstract: Imidazoleglycerol-phosphate dehydratase (IGPD; HisB), which catalyses the conversion of imidazoleglycerol-phosphate (IGP) to imidazoleacetol-phosphate in the histidine biosynthesis pathway, is absent in mammals. This feature makes it an attractive target for herbicide discovery. Here, the crystal structure of Mycobacterium tuberculosis (Mtb) IGPD is reported together with the first crystal structures of substrate-bound and inhibited (by 3-amino-1,2,4-triazole; ATZ) forms of IGPD from any organism. The overall tertiary structure of Mtb IGPD, a four-helix-bundle sandwiched between two four-stranded mixed β-sheets, resembles the three-dimensional structures of IPGD from other organisms; however, Mtb IGPD possesses a unique structural feature: the insertion of a one-turn 310-helix followed by a loop ten residues in length. The functional form of IGPD is 24-meric, exhibiting 432 point-group symmetry. The structure of the IGPD-IGP complex revealed that the imidazole ring of the IGP is firmly anchored between the two Mn atoms, that the rest of the substrate interacts through hydrogen bonds mainly with residues Glu21, Arg99, Glu180, Arg121 and Lys184 which protrude from three separate protomers and that the 24-mer assembly contains 24 catalytic centres. Both the structural and the kinetic data demonstrate that the inhibitor 3-amino-1,2,4-triazole inhibits IGPD competitively.
authors: Protein Crystallography Laboratory, National Institute of Immunology, Aruna Asaf Ali Marg, New Delhi 110 067, India.
authors: Mohammad Syed
authors: MS
authors: Ahangar
authors: Rajan
authors: R
authors: Vyas
authors: Nazia
authors: N
authors: Nasir
authors: Bichitra K
authors: BK
authors: Biswal
mesh_terms: D000640:Amitrole / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D006836:Hydro-Lyases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D011487:Protein Conformation; D013379:Substrate Specificity; D014376:Tuberculosis / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology*
chemical_list: D004791:Enzyme Inhibitors; D006836:Hydro-Lyases; C021434:imidazoleglycerolphosphate dehydratase; D000640:Amitrole
keywords: Mycobacterium tuberculosis; drug targets; enzyme inhibition