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Research article - Peer-reviewed, 2011

Structural and functional studies of mycobacterial IspD enzymes

Björkelid, Christofer; Bergfors, Terese; Henriksson, Lena M.; Stern, Ana Laura; Mowbray, Sherry; Unge, Torsten; Jones, T. Alwyn


A number of pathogens, including the causative agents of tuberculosis and malaria, synthesize isopentenyl diphosphate via the 2-C-methyl-D-erythritol 4-phosphate (MEP) pathway rather than the classical mevalonate pathway found in humans. As part of a structure-based drug-discovery program against tuberculosis, IspD, the enzyme that carries out the third step in the MEP pathway, was targeted. Constructs of both the Mycobacterium smegmatis and the Mycobacterium tuberculosis enzymes that were suitable for structural and inhibitor-screening studies were engineered. Two crystal structures of the M. smegmatis enzyme were produced, one in complex with CTP and the other in complex with CMP. In addition, the M. tuberculosis enzyme was crystallized in complex with CTP. Here, the structure determination and crystallographic refinement of these crystal forms and the enzymatic characterization of the M. tuberculosis enzyme construct are reported. A comparison with known IspD structures allowed the definition of the structurally conserved core of the enzyme. It indicates potential flexibility in the enzyme and in particular in areas close to the active site. These well behaved constructs provide tools for future target-based screening of potential inhibitors. The conserved nature of the extended active site suggests that any new inhibitor will potentially exhibit broad-spectrum activity.

Published in

Acta Crystallographica Section D: Biological Crystallography
2011, volume: 67, pages: 403-414

Authors' information

Björkelid, Christofer
Bergfors, Terese
Henriksson, Lena M.
Uppsala University
Stern, Ana Laura
Swedish University of Agricultural Sciences, Department of Molecular Biology
Mowbray, Sherry
Swedish University of Agricultural Sciences, Department of Molecular Biology
Unge, Torsten
Jones, T. Alwyn

Sustainable Development Goals

SDG3 Good health and well-being

UKÄ Subject classification

Biochemistry and Molecular Biology

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