8hy6
From Proteopedia
(Difference between revisions)
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| - | '''Unreleased structure''' | ||
| - | + | ==Crystal structure of B1 NDM-1 MBL in complex with 2-amino-5-phenethylthiazole-4-carboxylic acid== | |
| + | <StructureSection load='8hy6' size='340' side='right'caption='[[8hy6]], [[Resolution|resolution]] 1.40Å' scene=''> | ||
| + | == Structural highlights == | ||
| + | <table><tr><td colspan='2'>[[8hy6]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae Klebsiella pneumoniae]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=8HY6 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8HY6 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]] 1.4Å</td></tr> | ||
| + | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=5ZX:2-azanyl-5-(2-phenylethyl)-1,3-thiazole-4-carboxylic+acid'>5ZX</scene>, <scene name='pdbligand=GOL:GLYCEROL'>GOL</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=8hy6 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8hy6 OCA], [https://pdbe.org/8hy6 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8hy6 RCSB], [https://www.ebi.ac.uk/pdbsum/8hy6 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8hy6 ProSAT]</span></td></tr> | ||
| + | </table> | ||
| + | == Function == | ||
| + | [https://www.uniprot.org/uniprot/BLAN1_KLEPN BLAN1_KLEPN] Confers resistance to many beta-lactam antibiotics, including some carbapenems. Does not confer resistance to the polymixin colistin or the fluoroquinolone ciprofloxacin. | ||
| + | <div style="background-color:#fffaf0;"> | ||
| + | == Publication Abstract from PubMed == | ||
| + | Metallo-beta-lactamases (MBLs) are zinc-dependent enzymes capable of hydrolyzing all bicyclic beta-lactam antibiotics, posing a great threat to public health. However, there are currently no clinically approved MBL inhibitors. Despite variations in their active sites, MBLs share a common catalytic mechanism with carbapenems, forming similar reaction species and hydrolysates. We here report the development of 2-aminothiazole-4-carboxylic acids (AtCs) as broad-spectrum MBL inhibitors by mimicking the anchor pharmacophore features of carbapenem hydrolysate binding. Several AtCs manifested potent activity against B1, B2, and B3 MBLs. Crystallographic analyses revealed a common binding mode of AtCs with B1, B2, and B3 MBLs, resembling binding observed in the MBL-carbapenem product complexes. AtCs restored Meropenem activity against MBL-producing isolates. In the murine sepsis model, AtCs exhibited favorable synergistic efficacy with Meropenem, along with acceptable pharmacokinetics and safety profiles. This work offers promising lead compounds and a structural basis for the development of potential drug candidates to combat MBL-mediated antimicrobial resistance. | ||
| - | + | Discovery of 2-Aminothiazole-4-carboxylic Acids as Broad-Spectrum Metallo-beta-lactamase Inhibitors by Mimicking Carbapenem Hydrolysate Binding.,Yan YH, Zhang TT, Li R, Wang SY, Wei LL, Wang XY, Zhu KR, Li SR, Liang GQ, Yang ZB, Yang LL, Qin S, Li GB J Med Chem. 2023 Oct 12;66(19):13746-13767. doi: 10.1021/acs.jmedchem.3c01189. , Epub 2023 Oct 4. PMID:37791640<ref>PMID:37791640</ref> | |
| - | + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |
| - | [[Category: | + | </div> |
| - | [[Category: Li | + | <div class="pdbe-citations 8hy6" style="background-color:#fffaf0;"></div> |
| - | [[Category: Yan | + | == References == |
| - | [[Category: Zhu | + | <references/> |
| + | __TOC__ | ||
| + | </StructureSection> | ||
| + | [[Category: Klebsiella pneumoniae]] | ||
| + | [[Category: Large Structures]] | ||
| + | [[Category: Li G-B]] | ||
| + | [[Category: Yan Y-H]] | ||
| + | [[Category: Zhu K-R]] | ||
Current revision
Crystal structure of B1 NDM-1 MBL in complex with 2-amino-5-phenethylthiazole-4-carboxylic acid
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