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| | ==Structure of E. coli undecaprenyl diphosphate synthase in complex with BPH-1297== | | ==Structure of E. coli undecaprenyl diphosphate synthase in complex with BPH-1297== |
| - | <StructureSection load='4h38' size='340' side='right' caption='[[4h38]], [[Resolution|resolution]] 1.95Å' scene=''> | + | <StructureSection load='4h38' size='340' side='right'caption='[[4h38]], [[Resolution|resolution]] 1.95Å' scene=''> |
| | == Structural highlights == | | == Structural highlights == |
| - | <table><tr><td colspan='2'>[[4h38]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/"bacillus_coli"_migula_1895 "bacillus coli" migula 1895]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4H38 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4H38 FirstGlance]. <br> | + | <table><tr><td colspan='2'>[[4h38]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli Escherichia coli]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4H38 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4H38 FirstGlance]. <br> |
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=0YX:(5-BROMO-2-{[3-(OCTYLOXY)BENZYL]OXY}PHENYL)PHOSPHONIC+ACID'>0YX</scene></td></tr> | + | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=0YX:(5-BROMO-2-{[3-(OCTYLOXY)BENZYL]OXY}PHENYL)PHOSPHONIC+ACID'>0YX</scene></td></tr> |
| - | <tr id='related'><td class="sblockLbl"><b>[[Related_structure|Related:]]</b></td><td class="sblockDat">[[4h2j|4h2j]], [[4h2m|4h2m]], [[4h2o|4h2o]], [[4h3a|4h3a]], [[4h3c|4h3c]]</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=4h38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h38 OCA], [https://pdbe.org/4h38 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4h38 RCSB], [https://www.ebi.ac.uk/pdbsum/4h38 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4h38 ProSAT]</span></td></tr> |
| - | <tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">uppS, ispU, rth, yaeS, b0174, JW0169 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=562 "Bacillus coli" Migula 1895])</td></tr>
| + | |
| - | <tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Ditrans,polycis-undecaprenyl-diphosphate_synthase_((2E,6E)-farnesyl-_diphosphate_specific) Ditrans,polycis-undecaprenyl-diphosphate synthase ((2E,6E)-farnesyl- diphosphate specific)], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.5.1.31 2.5.1.31] </span></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=4h38 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4h38 OCA], [http://pdbe.org/4h38 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4h38 RCSB], [http://www.ebi.ac.uk/pdbsum/4h38 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4h38 ProSAT]</span></td></tr> | + | |
| | </table> | | </table> |
| | == Function == | | == Function == |
| - | [[http://www.uniprot.org/uniprot/UPPS_ECOLI UPPS_ECOLI]] Generates ditrans,octacis-undecaprenyl pyrophosphate (UPP) from isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP). UPP is the precursor of glycosyl carrier lipid in the biosynthesis of bacterial cell wall polysaccharide components such as peptidoglycan and lipopolysaccharide.<ref>PMID:12756244</ref> | + | [https://www.uniprot.org/uniprot/UPPS_ECOLI UPPS_ECOLI] Generates ditrans,octacis-undecaprenyl pyrophosphate (UPP) from isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP). UPP is the precursor of glycosyl carrier lipid in the biosynthesis of bacterial cell wall polysaccharide components such as peptidoglycan and lipopolysaccharide.<ref>PMID:12756244</ref> |
| | <div style="background-color:#fffaf0;"> | | <div style="background-color:#fffaf0;"> |
| | == Publication Abstract from PubMed == | | == Publication Abstract from PubMed == |
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| | __TOC__ | | __TOC__ |
| | </StructureSection> | | </StructureSection> |
| - | [[Category: Bacillus coli migula 1895]] | + | [[Category: Escherichia coli]] |
| - | [[Category: Oldfield, E]] | + | [[Category: Large Structures]] |
| - | [[Category: Zhu, W]] | + | [[Category: Oldfield E]] |
| - | [[Category: Alpha-helix]] | + | [[Category: Zhu W]] |
| - | [[Category: Cell wall biosynthesis]]
| + | |
| - | [[Category: Farnesyl diphosphate binding]]
| + | |
| - | [[Category: Isopentenyl diphosphate binding]]
| + | |
| - | [[Category: Prenyl transferase]]
| + | |
| - | [[Category: Prenyl transferase inhibitor complex]]
| + | |
| - | [[Category: Transferase-transferase inhibitor complex]]
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| Structural highlights
Function
UPPS_ECOLI Generates ditrans,octacis-undecaprenyl pyrophosphate (UPP) from isopentenyl pyrophosphate (IPP) and farnesyl diphosphate (FPP). UPP is the precursor of glycosyl carrier lipid in the biosynthesis of bacterial cell wall polysaccharide components such as peptidoglycan and lipopolysaccharide.[1]
Publication Abstract from PubMed
With the rise in resistance to antibiotics such as methicillin, there is a need for new drugs. We report here the discovery and X-ray crystallographic structures of 10 chemically diverse compounds (benzoic, diketo, and phosphonic acids, as well as a bisamidine and a bisamine) that inhibit bacterial undecaprenyl diphosphate synthase, an essential enzyme involved in cell wall biosynthesis. The inhibitors bind to one or more of the four undecaprenyl diphosphate synthase inhibitor binding sites identified previously, with the most active leads binding to site 4, outside the catalytic center. The most potent leads are active against Staphylococcus aureus [minimal inhibitory concentration (MIC)(90) approximately 0.25 microg/mL], and one potently synergizes with methicillin (fractional inhibitory concentration index = 0.25) and is protective in a mouse infection model. These results provide numerous leads for antibacterial development and open up the possibility of restoring sensitivity to drugs such as methicillin, using combination therapies.
Antibacterial drug leads targeting isoprenoid biosynthesis.,Zhu W, Zhang Y, Sinko W, Hensler ME, Olson J, Molohon KJ, Lindert S, Cao R, Li K, Wang K, Wang Y, Liu YL, Sankovsky A, de Oliveira CA, Mitchell DA, Nizet V, McCammon JA, Oldfield E Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):123-8. doi: 10.1073/pnas.1219899110. , Epub 2012 Dec 17. PMID:23248302[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
See Also
References
- ↑ Chang SY, Ko TP, Liang PH, Wang AH. Catalytic mechanism revealed by the crystal structure of undecaprenyl pyrophosphate synthase in complex with sulfate, magnesium, and triton. J Biol Chem. 2003 Aug 1;278(31):29298-307. Epub 2003 May 19. PMID:12756244 doi:10.1074/jbc.M302687200
- ↑ Zhu W, Zhang Y, Sinko W, Hensler ME, Olson J, Molohon KJ, Lindert S, Cao R, Li K, Wang K, Wang Y, Liu YL, Sankovsky A, de Oliveira CA, Mitchell DA, Nizet V, McCammon JA, Oldfield E. Antibacterial drug leads targeting isoprenoid biosynthesis. Proc Natl Acad Sci U S A. 2013 Jan 2;110(1):123-8. doi: 10.1073/pnas.1219899110. , Epub 2012 Dec 17. PMID:23248302 doi:http://dx.doi.org/10.1073/pnas.1219899110
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