6b04

<StructureSection load='6b04' size='340' side='right' caption='[[6b04]], [[Resolution|resolution]] 1.83&Aring;' scene=''>

<table><tr><td colspan='2'>[[6b04]] is a 3 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6B04 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6B04 FirstGlance]. <br>

</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=C6J:[2-(1-methylpyridin-2-yl)-1-phosphono-ethyl]phosphonic+acid'>C6J</scene>, <scene name='pdbligand=EDO:1,2-ETHANEDIOL'>EDO</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene></td></tr>

<tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[6b02|6b02]], [[6b06|6b06]], [[6b07|6b07]]</td></tr>

<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6b04 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6b04 OCA], [http://pdbe.org/6b04 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6b04 RCSB], [http://www.ebi.ac.uk/pdbsum/6b04 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6b04 ProSAT]</span></td></tr>

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== Publication Abstract from PubMed ==

Farnesyl diphosphate synthase (FPPS) is an enzyme from the class of short chain (E)-prenyltransferases that catalyzes the condensation of two molecules of isopentenyl diphosphate (IPP, C5) with dimethylallyl diphosphate (DMAPP, C5) to generate the C15 product FPP. In insects, FPPS plays a key role in the biosynthesis of the morphogenetic and gonadotropic "juvenile hormone" (JH). Lepidopteran genomes encode two very distinct FPPS paralogs, one of which ("type-II") is expressed almost exclusively in the JH-producing glands, the corpora allata. This paralog has been hypothesized to display structural features that enable the binding of the bulkier precursors required for the biosynthesis of lepidopteran ethyl-branched JHs. Here, we report on the first crystal structures of an insect FPPS solved to date. Apo, ligand-bound, and inhibitor-bound structures of type-II FPPS (FPPS2) from the spruce budworm, Choristoneura fumiferana (Order: Lepidoptera), were obtained. Comparison of apo and inhibitor-bound enzymes revealed differences in both inhibitor binding and structural plasticity of CfFPPS2 compared to other FPPSs. Our data showed that IPP is not essential to the closure of the C-terminal tail. Ortho-substituted pyridinium bisphosphonates, previously shown to inhibit CfFPPS2, bound to the allylic site, as predicted; however, their alkyl groups were oriented towards the homoallylic binding site, with the bulkier propyl-substituted inhibitor penetrating deeply into the IPP binding pocket. The current study sheds light on the structural basis of substrate specificity of type-II FPPS of the spruce budworm. Through a comparison with other inhibitor-bound FPPSs, we propose several approaches to improve inhibitor selectivity and potency.

 

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== References ==

[[Category: Cusson, M]]

[[Category: Picard, M E]]

[[Category: Shi, R]]

[[Category: Farnesyl diphosphate synthase]]

[[Category: Inhibitor design]]

[[Category: Transferase-transferase inhibitor complex]]