3OHI

Structure of Giardia fructose-1,6-biphosphate aldolase in complex with 3-hydroxy-2-pyridone

Summary for 3OHI

• Entry DOI: 10.2210/pdb3ohi/pdb
• Related: 2ISV 2ISW 3GAK 3GAY 3GB6
• Descriptor: Putative fructose-1,6-bisphosphate aldolase, ZINC ION, ({3-hydroxy-2-oxo-4-[2-(phosphonooxy)ethyl]pyridin-1(2H)-yl}methyl)phosphonic acid, ... (4 entities in total)
• Functional Keywords: class ii fructose-1, 6-bisphosphate aldolase, glycolytic pathway, lyase
• Biological source: Giardia intestinalis (Giardia intestinalis)
• Total number of polymer chains: 2
• Total formula weight: 71376.66

Authors

Herzberg, O.,Galkin, A. (deposition date: 2010-08-17, release date: 2011-01-19, Last modification date: 2023-09-06)

Primary citation

Li, Z.,Liu, Z.,Cho, D.W.,Zou, J.,Gong, M.,Breece, R.M.,Galkin, A.,Li, L.,Zhao, H.,Maestas, G.D.,Tierney, D.L.,Herzberg, O.,Dunaway-Mariano, D.,Mariano, P.S.
Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase.
J.Inorg.Biochem., 105:509-517, 2010

PubMed Abstract: Inhibitors of the Giardia lamblia fructose 1,6-bisphosphate aldolase (GlFBPA), which transforms fructose 1,6-bisphosphate (FBP) to dihydroxyacetone phosphate and glyceraldehyde 3-phosphate, were designed based on 3-hydroxy-2-pyridone and 1,2-dihydroxypyridine scaffolds that position two negatively charged tetrahedral groups for interaction with substrate phosphate binding residues, a hydrogen bond donor to the catalytic Asp83, and a Zn(2+) binding group. The inhibition activities for the GlFBPA catalyzed reaction of FBP of the prepared alkyl phosphonate/phosphate substituted 3-hydroxy-2-pyridinones and a dihydroxypyridine were determined. The 3-hydroxy-2-pyridone inhibitor 8 was found to bind to GlFBPA with an affinity (K(i)=14μM) that is comparable to that of FBP (K(m)=2μM) or its inert analog TBP (K(i)=1μM). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3Å) shows that 8 binds to the active site in the manner predicted by in silico docking with the exception of coordination with Zn(2+). The observed distances and orientation of the pyridone ring O=C-C-OH relative to Zn(2+) are not consistent with a strong interaction. To determine if Zn(2+)coordination occurs in the GlFBPA-inhibitor 8 complex in solution, EXAFS spectra were measured. A four coordinate geometry comprised of the three enzyme histidine ligands and an oxygen atom from the pyridone ring O=C-C-OH was indicated. Analysis of the Zn(2+) coordination geometries in recently reported structures of class II FBPAs suggests that strong Zn(2+) coordination is reserved for the enediolate-like transition state, accounting for minimal contribution of Zn(2+) coordination to binding of 8 to GlFBPA.

PubMed: 21333622
DOI: 10.1016/j.jinorgbio.2010.12.012

Experimental method

X-RAY DIFFRACTION (2.3 Å)