6x3c: Difference between revisions
New page: '''Unreleased structure''' The entry 6x3c is ON HOLD Authors: Chaires, H.A., Fraser, J.S. Description: Crystal structure of streptogramin A acetyltransferase VatA from Staphylococcus a... |
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The | ==Crystal structure of streptogramin A acetyltransferase VatA from Staphylococcus aureus in complex with streptogramin analog F1037 (47)== | ||
<StructureSection load='6x3c' size='340' side='right'caption='[[6x3c]], [[Resolution|resolution]] 3.05Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[6x3c]] is a 6 chain structure with sequence from [https://en.wikipedia.org/wiki/Staphylococcus_aureus Staphylococcus aureus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6X3C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6X3C 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]] 3.05Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=MG:MAGNESIUM+ION'>MG</scene>, <scene name='pdbligand=O7S:(3R,4R,5E,10E,12E,14S,16R,26aR)-16-fluoro-14-hydroxy-12-methyl-3-(propan-2-yl)-4-(prop-2-en-1-yl)-3,4,8,9,14,15,16,17,24,25,26,26a-dodecahydro-1H,7H,22H-21,18-(azeno)pyrrolo[2,1-c][1,8,4,19]dioxadiazacyclotetracosine-1,7,22-trione'>O7S</scene>, <scene name='pdbligand=PO4:PHOSPHATE+ION'>PO4</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene>, <scene name='pdbligand=SXA:THIOACETIC+ACID+S-{2-[3-(2-HYDROXY-3,3-DIMETHYL-4-PHOSPHONOOXY-BUTYRYLAMINO)-PROPIONYLAMINO]-ETHYL}+ESTER'>SXA</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=6x3c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6x3c OCA], [https://pdbe.org/6x3c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6x3c RCSB], [https://www.ebi.ac.uk/pdbsum/6x3c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6x3c ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/VATA_STAAU VATA_STAAU] Inactivates the A compounds of virginiamycin-like antibiotics, thus providing resistance to these antibiotics. | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Natural products serve as chemical blueprints for most antibiotics in clinical use. The evolutionary process by which these molecules arise is inherently accompanied by the co-evolution of resistance mechanisms that shorten the clinical lifetime of any given class of antibiotics(1). Virginiamycin acetyltransferase (Vat) enzymes are resistance proteins that provide protection against streptogramins(2), potent antibiotics against Gram-positive bacteria that inhibit the bacterial ribosome(3). Owing to the challenge of selectively modifying the chemically complex, 23-membered macrocyclic scaffold of group A streptogramins, analogues that overcome the resistance conferred by Vat enzymes have not been previously developed(2). Here we report the design, synthesis, and antibacterial evaluation of group A streptogramin antibiotics with extensive structural variability. Using cryo-electron microscopy and forcefield-based refinement, we characterize the binding of eight analogues to the bacterial ribosome at high resolution, revealing binding interactions that extend into the peptidyl tRNA-binding site and towards synergistic binders that occupy the nascent peptide exit tunnel. One of these analogues has excellent activity against several streptogramin-resistant strains of Staphylococcus aureus, exhibits decreased rates of acetylation in vitro, and is effective at lowering bacterial load in a mouse model of infection. Our results demonstrate that the combination of rational design and modular chemical synthesis can revitalize classes of antibiotics that are limited by naturally arising resistance mechanisms. | |||
Synthetic group A streptogramin antibiotics that overcome Vat resistance.,Li Q, Pellegrino J, Lee DJ, Tran AA, Chaires HA, Wang R, Park JE, Ji K, Chow D, Zhang N, Brilot AF, Biel JT, van Zundert G, Borrelli K, Shinabarger D, Wolfe C, Murray B, Jacobson MP, Muhle E, Chesneau O, Fraser JS, Seiple IB Nature. 2020 Oct;586(7827):145-150. doi: 10.1038/s41586-020-2761-3. Epub 2020 Sep, 23. PMID:32968273<ref>PMID:32968273</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 6x3c" style="background-color:#fffaf0;"></div> | ||
[[Category: Chaires | == References == | ||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Large Structures]] | |||
[[Category: Staphylococcus aureus]] | |||
[[Category: Chaires HA]] | |||
[[Category: Fraser JS]] | |||