6npf: Difference between revisions
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<StructureSection load='6npf' size='340' side='right'caption='[[6npf]], [[Resolution|resolution]] 2.57Å' scene=''> | <StructureSection load='6npf' size='340' side='right'caption='[[6npf]], [[Resolution|resolution]] 2.57Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6npf]] is a 6 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6NPF OCA]. For a <b>guided tour on the structure components</b> use [ | <table><tr><td colspan='2'>[[6npf]] is a 6 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=6NPF OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6NPF FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KVM:[(3S)-1-hydroxy-2,5-dioxopyrrolidin-3-yl]phosphonic+acid'>KVM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</scene | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.57Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=KVM:[(3S)-1-hydroxy-2,5-dioxopyrrolidin-3-yl]phosphonic+acid'>KVM</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=TLA:L(+)-TARTARIC+ACID'>TLA</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=6npf FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6npf OCA], [https://pdbe.org/6npf PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6npf RCSB], [https://www.ebi.ac.uk/pdbsum/6npf PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6npf ProSAT]</span></td></tr> | |||
<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[ | |||
</table> | </table> | ||
== Function == | == Function == | ||
[ | [https://www.uniprot.org/uniprot/ENO_ECOLI ENO_ECOLI] Catalyzes the reversible conversion of 2-phosphoglycerate into phosphoenolpyruvate. It is essential for the degradation of carbohydrates via glycolysis. It is also a component of the RNA degradosome, a multi-enzyme complex involved in RNA processing and messenger RNA degradation. Its interaction with RNase E is important for the turnover of mRNA, in particular on transcripts encoding enzymes of energy-generating metabolic routes. Its presence in the degradosome is required for the response to excess phosphosugar. May play a regulatory role in the degradation of specific RNAs, such as ptsG mRNA, therefore linking cellular metabolic status with post-translational gene regulation.<ref>PMID:8610017</ref> <ref>PMID:14981237</ref> <ref>PMID:15522087</ref> | ||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Many years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery. | |||
Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate.,Krucinska J, Lombardo MN, Erlandsen H, Hazeen A, Duay SS, Pattis JG, Robinson VL, May ER, Wright DL Sci Rep. 2019 Nov 19;9(1):17106. doi: 10.1038/s41598-019-53301-3. PMID:31745118<ref>PMID:31745118</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
</div> | |||
<div class="pdbe-citations 6npf" style="background-color:#fffaf0;"></div> | |||
==See Also== | |||
*[[Enolase 3D structures|Enolase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Escherichia coli]] | |||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Erlandsen H]] | |||
[[Category: Erlandsen | [[Category: Krucinska J]] | ||
[[Category: Krucinska | [[Category: Lombardo M]] | ||
[[Category: Lombardo | [[Category: Wright D]] | ||
[[Category: Wright | |||
Latest revision as of 09:57, 11 October 2023
Structure of E.coli enolase in complex with an analog of the natural product SF-2312 metabolite.Structure of E.coli enolase in complex with an analog of the natural product SF-2312 metabolite.
Structural highlights
FunctionENO_ECOLI Catalyzes the reversible conversion of 2-phosphoglycerate into phosphoenolpyruvate. It is essential for the degradation of carbohydrates via glycolysis. It is also a component of the RNA degradosome, a multi-enzyme complex involved in RNA processing and messenger RNA degradation. Its interaction with RNase E is important for the turnover of mRNA, in particular on transcripts encoding enzymes of energy-generating metabolic routes. Its presence in the degradosome is required for the response to excess phosphosugar. May play a regulatory role in the degradation of specific RNAs, such as ptsG mRNA, therefore linking cellular metabolic status with post-translational gene regulation.[1] [2] [3] Publication Abstract from PubMedMany years ago, the natural secondary metabolite SF2312, produced by the actinomycete Micromonospora, was reported to display broad spectrum antibacterial properties against both Gram-positive and Gram-negative bacteria. Recent studies have revealed that SF2312, a natural phosphonic acid, functions as a potent inhibitor of human enolase. The mechanism of SF2312 inhibition of bacterial enolase and its role in bacterial growth and reproduction, however, have remained elusive. In this work, we detail a structural analysis of E. coli enolase bound to both SF2312 and its oxidized imide-form. Our studies support a model in which SF2312 acts as an analog of a high energy intermediate formed during the catalytic process. Biochemical, biophysical, computational and kinetic characterization of these compounds confirm that altering features characteristic of a putative carbanion (enolate) intermediate significantly reduces the potency of enzyme inhibition. When SF2312 is combined with fosfomycin in the presence of glucose-6 phosphate, significant synergy is observed. This suggests the two agents could be used as a potent combination, targeting distinct cellular mechanism for the treatment of bacterial infections. Together, our studies rationalize the structure-activity relationships for these phosphonates and validate enolase as a promising target for antibiotic discovery. Functional and structural basis of E. coli enolase inhibition by SF2312: a mimic of the carbanion intermediate.,Krucinska J, Lombardo MN, Erlandsen H, Hazeen A, Duay SS, Pattis JG, Robinson VL, May ER, Wright DL Sci Rep. 2019 Nov 19;9(1):17106. doi: 10.1038/s41598-019-53301-3. PMID:31745118[4] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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