7qq3
From Proteopedia
(Difference between revisions)
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== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[7qq3]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ3 FirstGlance]. <br> | <table><tr><td colspan='2'>[[7qq3]] is a 10 chain structure with sequence from [https://en.wikipedia.org/wiki/Escherichia_coli_K-12 Escherichia coli K-12]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ3 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ3 FirstGlance]. <br> | ||
| - | </td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MG:1N-METHYLGUANOSINE-5-MONOPHOSPHATE'>1MG</scene>, <scene name='pdbligand=2MA:2-METHYLADENOSINE-5-MONOPHOSPHATE'>2MA</scene>, <scene name='pdbligand=2MG:2N-METHYLGUANOSINE-5-MONOPHOSPHATE'>2MG</scene>, <scene name='pdbligand=5MC:5-METHYLCYTIDINE-5-MONOPHOSPHATE'>5MC</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene>, <scene name='pdbligand=AG2:AGMATINE'>AG2</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=DHV:3-HYDROXY-D-VALINE'>DHV</scene>, <scene name='pdbligand=DVA:D-VALINE'>DVA</scene>, <scene name='pdbligand=IB9: | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Electron Microscopy, [[Resolution|Resolution]] 2.1Å</td></tr> |
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=1MG:1N-METHYLGUANOSINE-5-MONOPHOSPHATE'>1MG</scene>, <scene name='pdbligand=2MA:2-METHYLADENOSINE-5-MONOPHOSPHATE'>2MA</scene>, <scene name='pdbligand=2MG:2N-METHYLGUANOSINE-5-MONOPHOSPHATE'>2MG</scene>, <scene name='pdbligand=5MC:5-METHYLCYTIDINE-5-MONOPHOSPHATE'>5MC</scene>, <scene name='pdbligand=5MU:5-METHYLURIDINE+5-MONOPHOSPHATE'>5MU</scene>, <scene name='pdbligand=AG2:AGMATINE'>AG2</scene>, <scene name='pdbligand=DAL:D-ALANINE'>DAL</scene>, <scene name='pdbligand=DAR:D-ARGININE'>DAR</scene>, <scene name='pdbligand=DHV:3-HYDROXY-D-VALINE'>DHV</scene>, <scene name='pdbligand=DVA:D-VALINE'>DVA</scene>, <scene name='pdbligand=IB9:(3~{S})-3-azanyl-3-(4-hydroxyphenyl)propanoic+acid'>IB9</scene>, <scene name='pdbligand=IVA:ISOVALERIC+ACID'>IVA</scene>, <scene name='pdbligand=MAA:N-METHYL-L-ALANINE'>MAA</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=OMC:O2-METHYLYCYTIDINE-5-MONOPHOSPHATE'>OMC</scene>, <scene name='pdbligand=OMG:O2-METHYLGUANOSINE-5-MONOPHOSPHATE'>OMG</scene>, <scene name='pdbligand=OMU:O2-METHYLURIDINE+5-MONOPHOSPHATE'>OMU</scene>, <scene name='pdbligand=PSU:PSEUDOURIDINE-5-MONOPHOSPHATE'>PSU</scene>, <scene name='pdbligand=RX9:(~{E})-2-azanyl-3-methyl-pent-2-enoic+acid'>RX9</scene>, <scene name='pdbligand=RXL:2-azanyl-3-methyl-but-2-enoic+acid'>RXL</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=7qq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq3 OCA], [https://pdbe.org/7qq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq3 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq3 ProSAT]</span></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=7qq3 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq3 OCA], [https://pdbe.org/7qq3 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq3 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq3 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq3 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
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Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent. | Resistance of bacterial pathogens against antibiotics is declared by WHO as a major global health threat. As novel antibacterial agents are urgently needed, we re-assessed the broad-spectrum myxobacterial antibiotic myxovalargin and found it to be extremely potent against Mycobacterium tuberculosis. To ensure compound supply for further development, we studied myxovalargin biosynthesis in detail enabling production via fermentation of a native producer. Feeding experiments as well as functional genomics analysis suggested a structural revision, which was eventually corroborated by the development of a concise total synthesis. The ribosome was identified as the molecular target based on resistant mutant sequencing, and a cryo-EM structure revealed that myxovalargin binds within and completely occludes the exit tunnel, consistent with a mode of action to arrest translation during a late stage of translation initiation. These studies open avenues for structure-based scaffold improvement toward development as an antibacterial agent. | ||
| - | The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition.,Koller TO, Scheid U, Kosel T, Herrmann J, Krug D, Boshoff HIM, Beckert B, Evans JC, Schlemmer J, Sloan B, Weiner DM, Via LE, Moosa A, Ioerger TR, Graf M, Zinshteyn B, Abdelshahid M, Nguyen F, Arenz S, Gille F, Siebke M, Seedorf T, Plettenburg O, Green R, Warnke AL, Ullrich J, Warrass R, Barry CE 3rd, Warner DF, Mizrahi V, Kirschning A, Wilson DN, Muller R J Am Chem Soc. 2023 Jan | + | The Myxobacterial Antibiotic Myxovalargin: Biosynthesis, Structural Revision, Total Synthesis, and Molecular Characterization of Ribosomal Inhibition.,Koller TO, Scheid U, Kosel T, Herrmann J, Krug D, Boshoff HIM, Beckert B, Evans JC, Schlemmer J, Sloan B, Weiner DM, Via LE, Moosa A, Ioerger TR, Graf M, Zinshteyn B, Abdelshahid M, Nguyen F, Arenz S, Gille F, Siebke M, Seedorf T, Plettenburg O, Green R, Warnke AL, Ullrich J, Warrass R, Barry CE 3rd, Warner DF, Mizrahi V, Kirschning A, Wilson DN, Muller R J Am Chem Soc. 2023 Jan 18;145(2):851-863. doi: 10.1021/jacs.2c08816. Epub 2023 , Jan 5. PMID:36603206<ref>PMID:36603206</ref> |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | ||
Current revision
Cryo-EM structure of the E.coli 50S ribosomal subunit in complex with the antibiotic Myxovalargin A.
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