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Free keywords:
Isoprenoid biosynthesis; GcpE; Iron–sulfur cluster; X-ray structure; Drug design
Abstract:
Isoprenoid precursor biosynthesis occurs through the mevalonate or the methylerythritol phosphate (MEP) pathway, used i.e., by humans and by many human pathogens, respectively. In the MEP pathway, 2-C-methyl-D-erythritol-2,4-cyclo-diphosphate (MEcPP) is converted to (E)-1-hydroxy-2-methyl-but-2-enyl-4-diphosphate (HMBPP) by the iron–sulfur cluster enzyme HMBPP synthase (GcpE). The presented X-ray structure of the GcpE–MEcPP complex from Thermus thermophilus at 1.55 Å resolution provides valuable information about the catalytic mechanism and for rational inhibitor design. MEcPP binding inside the TIM-barrel funnel induces a 60° rotation of the [4Fe–4S] cluster containing domain onto the TIM-barrel entrance. The apical iron of the [4Fe–4S] cluster ligates with the C3 oxygen atom of MEcPP.
