9h2z
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of APH(2")-IVa alternate (soaking with EK3-18 inhibitor)== | |
| + | <StructureSection load='9h2z' size='340' side='right'caption='[[9h2z]], [[Resolution|resolution]] 2.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[9h2z]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Enterococcus_casseliflavus Enterococcus casseliflavus]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=9H2Z OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=9H2Z 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]] 2.4Å</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=9h2z FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=9h2z OCA], [https://pdbe.org/9h2z PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=9h2z RCSB], [https://www.ebi.ac.uk/pdbsum/9h2z PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=9h2z ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/O68183_ENTCA O68183_ENTCA] | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Aminoglycoside-phosphotransferases (APHs) are a class of bacterial enzymes that mediate acquired resistance to aminoglycoside antibiotics. Here we report the identification of small molecules counteracting aminoglycoside resistance in Enterococcus casseliflavus. Molecular dynamics simulations were performed to identify an allosteric pocket in three APH enzymes belonging to 3' and 2'' subfamilies in which we then screened, in silico, 12,000 small molecules. From a subset of only 14 high-scored molecules tested in vitro, we identified a compound, named here EK3, able to non-competitively inhibit the APH(2'')-IVa, an enzyme mediating clinical gentamicin resistance. Structure-activity relationship (SAR) exploration of this hit compound allowed us to identify a molecule with improved enzymatic inhibition. By measuring bacterial sensitivity, we found that the three best compounds in this series restored bactericidal activity of various aminoglycosides, including gentamicin, without exhibiting toxicity to HeLa cells. This work not only provides a basis to fight aminoglycoside resistance but also highlights a proof-of-concept for the search of allosteric modulators by using in silico methods. | ||
| - | + | APH Inhibitors that Reverse Aminoglycoside Resistance in Enterococcus casseliflavus.,Kaplan E, Chaloin L, Guichou JF, Berrou K, Rahimova R, Labesse G, Lionne C ChemMedChem. 2025 Jan 13:e202400842. doi: 10.1002/cmdc.202400842. PMID:39801466<ref>PMID:39801466</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| + | <div class="pdbe-citations 9h2z" style="background-color:#fffaf0;"></div> | ||
| + | == References == | ||
| + | <references/> | ||
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Enterococcus casseliflavus]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Chaloin L]] | ||
| + | [[Category: Gelin M]] | ||
| + | [[Category: Guichou J-F]] | ||
| + | [[Category: Kaplan E]] | ||
| + | [[Category: Lionne C]] | ||
Current revision
Crystal structure of APH(2")-IVa alternate (soaking with EK3-18 inhibitor)
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