3ohi: Difference between revisions

<StructureSection load='3ohi' size='340' side='right'caption='[[3ohi]], [[Resolution|resolution]] 2.30&Aring;' scene=''>

<table><tr><td colspan='2'>[[3ohi]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Giardia_intestinalis Giardia intestinalis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=3OHI OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=3OHI FirstGlance]. <br>

</td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.3&#8491;</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=HDX:({3-HYDROXY-2-OXO-4-[2-(PHOSPHONOOXY)ETHYL]PYRIDIN-1(2H)-YL}METHYL)PHOSPHONIC+ACID'>HDX</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</scene></td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=3ohi FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=3ohi OCA], [https://pdbe.org/3ohi PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=3ohi RCSB], [https://www.ebi.ac.uk/pdbsum/3ohi PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=3ohi ProSAT]</span></td></tr>

<div style="background-color:#fffaf0;">

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)=14muM) that is comparable to that of FBP (K(m)=2muM) or its inert analog TBP (K(i)=1muM). The X-ray structure of the GlFBPA-inhibitor 8 complex (2.3A) 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.

Rational design, synthesis and evaluation of first generation inhibitors of the Giardia lamblia fructose-1,6-biphosphate aldolase.,Li Z, Liu Z, Cho DW, Zou J, Gong M, Breece RM, Galkin A, Li L, Zhao H, Maestas GD, Tierney DL, Herzberg O, Dunaway-Mariano D, Mariano PS J Inorg Biochem. 2010 Dec 30;105(4):509-517. PMID:21333622<ref>PMID:21333622</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>

</div>

<div class="pdbe-citations 3ohi" style="background-color:#fffaf0;"></div>

== References ==

[[Category: Galkin A]]

[[Category: Herzberg O]]