2c07
From Proteopedia
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| - | [[Image:2c07.gif|left|200px]] | ||
| - | + | ==Oxoacyl-ACP reductase of Plasmodium falciparum== | |
| - | + | <StructureSection load='2c07' size='340' side='right'caption='[[2c07]], [[Resolution|resolution]] 1.50Å' scene=''> | |
| - | + | == Structural highlights == | |
| - | + | <table><tr><td colspan='2'>[[2c07]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Plasmodium_falciparum_3D7 Plasmodium falciparum 3D7]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2C07 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=2C07 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]] 1.5Å</td></tr> | |
| - | - | + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=2c07 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=2c07 OCA], [https://pdbe.org/2c07 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=2c07 RCSB], [https://www.ebi.ac.uk/pdbsum/2c07 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=2c07 ProSAT]</span></td></tr> | |
| - | + | </table> | |
| - | ''' | + | == Function == |
| - | + | [https://www.uniprot.org/uniprot/Q8I2S7_PLAF7 Q8I2S7_PLAF7] | |
| - | + | == Evolutionary Conservation == | |
| - | == | + | [[Image:Consurf_key_small.gif|200px|right]] |
| + | Check<jmol> | ||
| + | <jmolCheckbox> | ||
| + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/c0/2c07_consurf.spt"</scriptWhenChecked> | ||
| + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> | ||
| + | <text>to colour the structure by Evolutionary Conservation</text> | ||
| + | </jmolCheckbox> | ||
| + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=2c07 ConSurf]. | ||
| + | <div style="clear:both"></div> | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
Type II fatty acid biosynthesis represents an attractive target for the discovery of new antimalarial drugs. Previous studies have identified malarial ENR (enoyl acyl-carrier-protein reductase, or FabI) as the target for the antiseptic triclosan. In the present paper, we report the biochemical properties and 1.5 A (1 A=0.1 nm) crystal structure of OAR (3-oxoacyl acyl-carrier-protein reductase, or FabG), the second reductive step in fatty acid biosynthesis and its inhibition by hexachlorophene. Under optimal conditions of pH and ionic strength, Plasmodium falciparum OAR displays kinetic properties similar to those of OAR from bacteria or plants. Activity with NADH is <3% of that with NADPH. Fluorescence enhancement studies indicate that NADPH can bind to the free enzyme, consistent with kinetic and product inhibition studies suggesting a steady-state ordered mechanism. The crystal structure reveals a tetramer with a sulphate ion bound in the cofactor-binding site such that the side chains of the catalytic triad of serine, tyrosine and lysine are aligned in an active conformation, as previously observed in the Escherichia coli OAR-NADP+ complex. A cluster of positively charged residues is positioned at the entrance to the active site, consistent with the proposed recognition site for the physiological substrate (3-oxoacyl-acyl-carrier protein) in E. coli OAR. The antibacterial and anthelminthic agent hexachlorophene is a potent inhibitor of OAR (IC50 2.05 microM) displaying non-linear competitive inhibition with respect to NADPH. Hexachlorophene (EC50 6.2 microM) and analogues such as bithionol also have antimalarial activity in vitro, suggesting they might be useful leads for further development. | Type II fatty acid biosynthesis represents an attractive target for the discovery of new antimalarial drugs. Previous studies have identified malarial ENR (enoyl acyl-carrier-protein reductase, or FabI) as the target for the antiseptic triclosan. In the present paper, we report the biochemical properties and 1.5 A (1 A=0.1 nm) crystal structure of OAR (3-oxoacyl acyl-carrier-protein reductase, or FabG), the second reductive step in fatty acid biosynthesis and its inhibition by hexachlorophene. Under optimal conditions of pH and ionic strength, Plasmodium falciparum OAR displays kinetic properties similar to those of OAR from bacteria or plants. Activity with NADH is <3% of that with NADPH. Fluorescence enhancement studies indicate that NADPH can bind to the free enzyme, consistent with kinetic and product inhibition studies suggesting a steady-state ordered mechanism. The crystal structure reveals a tetramer with a sulphate ion bound in the cofactor-binding site such that the side chains of the catalytic triad of serine, tyrosine and lysine are aligned in an active conformation, as previously observed in the Escherichia coli OAR-NADP+ complex. A cluster of positively charged residues is positioned at the entrance to the active site, consistent with the proposed recognition site for the physiological substrate (3-oxoacyl-acyl-carrier protein) in E. coli OAR. The antibacterial and anthelminthic agent hexachlorophene is a potent inhibitor of OAR (IC50 2.05 microM) displaying non-linear competitive inhibition with respect to NADPH. Hexachlorophene (EC50 6.2 microM) and analogues such as bithionol also have antimalarial activity in vitro, suggesting they might be useful leads for further development. | ||
| - | + | Kinetic, inhibition and structural studies on 3-oxoacyl-ACP reductase from Plasmodium falciparum, a key enzyme in fatty acid biosynthesis.,Wickramasinghe SR, Inglis KA, Urch JE, Muller S, van Aalten DM, Fairlamb AH Biochem J. 2006 Jan 15;393(Pt 2):447-57. PMID:16225460<ref>PMID:16225460</ref> | |
| - | + | ||
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | + | </div> | |
| - | [[Category: | + | <div class="pdbe-citations 2c07" style="background-color:#fffaf0;"></div> |
| - | [[Category: | + | == References == |
| - | + | <references/> | |
| - | [[Category: Fairlamb | + | __TOC__ |
| - | [[Category: Inglis | + | </StructureSection> |
| - | [[Category: Muller | + | [[Category: Large Structures]] |
| - | [[Category: Urch | + | [[Category: Plasmodium falciparum 3D7]] |
| - | [[Category: Wickramasinghe | + | [[Category: Fairlamb AH]] |
| - | [[Category: | + | [[Category: Inglis KA]] |
| - | + | [[Category: Muller S]] | |
| - | + | [[Category: Urch JE]] | |
| - | + | [[Category: Wickramasinghe SR]] | |
| - | + | [[Category: Van Aalten DMF]] | |
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Current revision
Oxoacyl-ACP reductase of Plasmodium falciparum
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