Structures of Leishmania Fructose-1,6-Bisphosphatase Reveal Species-Specific Differences in the Mechanism of Allosteric Inhibition

Meng Yuan, Montserrat G. Vásquez-Valdivieso, Iain W. McNae, Paul A.M. Michels, Linda A. Fothergill-Gilmore, Malcolm D. Walkinshaw*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

The gluconeogenic enzyme fructose-1,6-bisphosphatase has been proposed as a potential drug target against Leishmania parasites that cause up to 20,000-30,000 deaths annually. A comparison of three crystal structures of Leishmania major fructose-1,6-bisphosphatase (LmFBPase) along with enzyme kinetic data show how AMP acts as an allosteric inhibitor and provides insight into its metal-dependent reaction mechanism. The crystal structure of the apoenzyme form of LmFBPase is a homotetramer in which the dimer of dimers adopts a planar conformation with disordered "dynamic loops". The structure of LmFBPase, complexed with manganese and its catalytic product phosphate, shows the dynamic loops locked into the active sites. A third crystal structure of LmFBPase complexed with its allosteric inhibitor AMP shows an inactive form of the tetramer, in which the dimer pairs are rotated by 18° relative to each other. The three structures suggest an allosteric mechanism in which AMP binding triggers a rearrangement of hydrogen bonds across the large and small interfaces. Retraction of the "effector loop" required for AMP binding releases the side chain of His23 from the dimer-dimer interface. This is coupled with a flip of the side chain of Arg48 which ties down the key catalytic dynamic loop in a disengaged conformation and also locks the tetramer in an inactive rotated T-state. The structure of the effector site of LmFBPase shows different structural features compared with human FBPases, thereby offering a potential and species-specific drug target.

Original languageEnglish
Pages (from-to)3075-3089
JournalJournal of Molecular Biology
Issue number20
Early online date4 Sept 2017
Publication statusPublished - 13 Oct 2017

Keywords / Materials (for Non-textual outputs)

  • Allostery
  • Crystal structure
  • Enzyme kinetics
  • Gluconeogenesis
  • Leishmaniasis


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