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

Matthias Lee, Tobias Gräwert*, Felix Quitterer, Felix Rohdich, Jorg Eppinger, Wolfgang Eisenreich, Adelbert Bacher, Michael Groll

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

49 Scopus citations

Abstract

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 110 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.

Original languageEnglish (US)
Pages (from-to)600-610
Number of pages11
JournalJournal of Molecular Biology
Volume404
Issue number4
DOIs
StatePublished - Dec 10 2010

Keywords

  • GcpE protein
  • Iron-sulfur protein
  • Methylerythritol phosphate pathway
  • Non-mevalonate pathway
  • Terpene biosynthesis

ASJC Scopus subject areas

  • Molecular Biology

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