5OEZ

Crystal structure of Leishmania major fructose-1,6-bisphosphatase in apo form.

Summary for 5OEZ

• Entry DOI: 10.2210/pdb5oez/pdb
• Descriptor: FBP protein (2 entities in total)
• Functional Keywords: allostery, gluconeogenesis, hydrolase
• Biological source: Leishmania major
• Total number of polymer chains: 4
• Total formula weight: 155489.53

Authors

Yuan, M.,Vasquez-Valdivieso, M.G.,McNae, I.W.,Michels, P.A.M.,Fothergill-Gilmore, L.A.,Walkinshaw, M.D. (deposition date: 2017-07-10, release date: 2017-09-20, Last modification date: 2024-01-17)

Primary citation

Yuan, M.,Vasquez-Valdivieso, M.G.,McNae, I.W.,Michels, P.A.M.,Fothergill-Gilmore, L.A.,Walkinshaw, M.D.
Structures of Leishmania Fructose-1,6-Bisphosphatase Reveal Species-Specific Differences in the Mechanism of Allosteric Inhibition.
J. Mol. Biol., 429:3075-3089, 2017

PubMed 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 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.

PubMed: 28882541
DOI: 10.1016/j.jmb.2017.08.010

Experimental method

X-RAY DIFFRACTION (2.41 Å)