Biosynthesis of Isoprenoids: Crystal Structure of the [4Fe–4S] Cluster Protein IspG

Biosynthesis of Isoprenoids: Crystal Structure of the [4Fe–4S] Cluster Protein IspG

Biosynthesis of Isoprenoids: Crystal Structure of the [4Fe–4S] Cluster Protein IspG
M. Lee, T. Gräwert, F. Quitterer, F. Rohdich, J. Eppinger, W. Eisenreich, A. Bacher, M. Groll
Journal of Molecular Biology, Volume 404, Issue 4, Pages 600–610, (2010)
M. Lee, T. Gräwert, F. Quitterer, F. Rohdich, J. Eppinger, W. Eisenreich, A. Bacher, M. Groll
GcpE protein, Iron–sulfur protein, Non-mevalonate pathway, Methylerythritol phosphate pathway
2010
IspG protein serves as the penultimate enzyme of the recently discovered non-mevalonate pathway for the biosynthesis of the universal isoprenoid precursors, isopentenyl diphosphate and dimethylallyl diphosphate. The enzyme catalyzes the reductive ring opening of 2C-methyl-d-erythritol 2,4-cyclodiphosphate, which affords 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate. The protein was crystallized under anaerobic conditions, and its three-dimensional structure was determined to a resolution of 2.7 Å. Each subunit of the c2 symmetric homodimer folds into two domains connected by a short linker sequence. The N-terminal domain (N domain) is an eight-stranded β barrel that belongs to the large TIM-barrel superfamily. The C-terminal domain (C domain) consists of a β sheet that is flanked on both sides by helices. One glutamate and three cysteine residues of the C domain coordinate a [4Fe–4S] cluster. Homodimer formation involves an extended contact area (about 1100 Å2) between helices 8 and 9 of each respective β barrel. Moreover, each C domain contacts the N domain of the partner subunit, but the interface regions are small (about 430 Å2). We propose that the enzyme substrate binds to the positively charged surface area at the C-terminal pole of the β barrel. The C domain carrying the iron–sulfur cluster could then move over to form a closed conformation where the substrate is sandwiched between the N domain and the C domain. This article completes the set of three-dimensional structures of the non-mevalonate pathway enzymes, which are of specific interest as potential targets for tuberculostatic and antimalarial drugs.
 
 
 
10.1016/j.jmb.2010.09.050
00222836