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

DOI: 10.1016/j.jmb.2017.08.010 DOI Help

Authors: Meng Yuan (University of Edinburgh) , Monserrat G. Vasquez-valdivieso (University of Edinburgh) , Iain Mcnae (University of Edinburgh) , Paul A. M. Michels (University of Edinburgh) , Linda A. Fothergill-gilmore (University of Edinburgh) , Malcolm D. Walkinshaw (University of Edinburgh)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Journal Of Molecular Biology

State: Published (Approved)
Published: September 2017
Diamond Proposal Number(s): 13550

Open Access Open Access

Abstract: 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 L. 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.

Subject Areas: Biology and Bio-materials


Instruments: I03-Macromolecular Crystallography , I04-Macromolecular Crystallography

Documents:
1-s2.0-S0022283617304163-main.pdf