Acta Crystallographica Section D

Biological Crystallography

Volume 69, Part 12 (December 2013)

research papers

Acta Cryst. (2013). D69, 2461-2467    [ doi:10.1107/S0907444913022579 ]

Structures of native, substrate-bound and inhibited forms of Mycobacterium tuberculosis imidazoleglycerol-phosphate dehydratase

M. S. Ahangar, R. Vyas, N. Nasir and B. K. Biswal

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 [beta]-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.

PDB references: 4gqu, 4lom and 4lpf

Keywords: drug targets; enzyme inhibition; Mycobacterium tuberculosis.

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[ doi:10.1107/S0907444913022579/mv5093sup1.tif ]
Supplementary Fig. S1. Histidine-biosynthesis pathway. A schematic representation of the histidine-biosynthesis pathway in prokaryotes and plants is shown. 11 enzymatic steps which lead to histidine biosynthesis are shown by arrows. The starting metabolite 5-phosphoribosyl-1-pyrophosphate, the eventual product histidine and the nine reaction intermediates are shown as stick models. The enzymes of each step and their corresponding gene IDs in the Mtb genome are also mentioned. Also shown in ribbon representation are the three-dimensional structures of the Mtb enzymes elucidated thus far.

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Supplementary Fig. S2. Comparison of the crystal structures. Overlay of the monomeric three-dimensional structures of IGPD from Mtb (pink), A. thaliana (cyan; PDB entry 2f1d), F. neoformans (light green; PDB entry 1rhy) and S. aureus (light blue; PDB entry 2ae8).

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Supplementary Fig. S3. DLS profile of Mtb IGPD. The results clearly suggest that Mtb IGPD exists as a 24-mer in solution.

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Supplementary Fig. S4. Sequence alignment of Mtb IGPD and its counterparts from A. thaliana, F. neoformans and S. aureus. Conserved residues are highlighted in the red box.


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