6dd1: Difference between revisions
No edit summary |
No edit summary |
||
| Line 3: | Line 3: | ||
<StructureSection load='6dd1' size='340' side='right'caption='[[6dd1]], [[Resolution|resolution]] 1.70Å' scene=''> | <StructureSection load='6dd1' size='340' side='right'caption='[[6dd1]], [[Resolution|resolution]] 1.70Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'>[[6dd1]] is a 2 chain structure with sequence from [ | <table><tr><td colspan='2'>[[6dd1]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Pseudomonas_aeruginosa Pseudomonas aeruginosa]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6DD1 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6DD1 FirstGlance]. <br> | ||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=M3Q:[(quinolin-8-yl)methyl]phosphonic+acid'>M3Q</scene>, <scene name='pdbligand=ZN:ZINC+ION'>ZN</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]] 1.7Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=ACT:ACETATE+ION'>ACT</scene>, <scene name='pdbligand=M3Q:[(quinolin-8-yl)methyl]phosphonic+acid'>M3Q</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'>[ | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=6dd1 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6dd1 OCA], [https://pdbe.org/6dd1 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6dd1 RCSB], [https://www.ebi.ac.uk/pdbsum/6dd1 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6dd1 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
== Function == | |||
[https://www.uniprot.org/uniprot/Q9K2N0_PSEAI Q9K2N0_PSEAI] | |||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
| Line 17: | Line 19: | ||
</div> | </div> | ||
<div class="pdbe-citations 6dd1" style="background-color:#fffaf0;"></div> | <div class="pdbe-citations 6dd1" style="background-color:#fffaf0;"></div> | ||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | == References == | ||
<references/> | <references/> | ||
| Line 22: | Line 27: | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: | [[Category: Pseudomonas aeruginosa]] | ||
[[Category: | [[Category: Chen Y]] | ||
[[Category: | [[Category: Pemberton OA]] | ||
Latest revision as of 09:03, 11 October 2023
Crystal structure of VIM-2 complexed with compound 14Crystal structure of VIM-2 complexed with compound 14
Structural highlights
FunctionPublication Abstract from PubMedGram-negative pathogens expressing serine beta-lactamases (SBLs) and metallo-beta-lactamases (MBLs), especially those with carbapenemase activity, threaten the clinical utility of almost all beta-lactam antibiotics. Here we describe the discovery of a heteroaryl phosphonate scaffold that exhibits noncovalent cross-class inhibition of representative carbapenemases, specifically the SBL KPC-2 and the MBLs NDM-1 and VIM-2. The most potent lead, compound 16, exhibited low nM to low muM inhibition of KPC-2, NDM-1, and VIM-2. Compound 16 potentiated imipenem efficacy against resistant clinical and laboratory bacterial strains expressing carbapenemases while showing some cytotoxicity toward human HEK293T cells only at concentrations above 100 mug/mL. Complex structures with KPC-2, NDM-1, and VIM-2 demonstrate how these inhibitors achieve high binding affinity to both enzyme classes. These findings provide a structurally and mechanistically new scaffold for drug discovery targeting multidrug resistant Gram-negative pathogens and more generally highlight the active site features of carbapenemases that can be leveraged for lead discovery. Heteroaryl Phosphonates as Noncovalent Inhibitors of Both Serine- and Metallocarbapenemases.,Pemberton OA, Jaishankar P, Akhtar A, Adams JL, Shaw LN, Renslo AR, Chen Y J Med Chem. 2019 Sep 26;62(18):8480-8496. doi: 10.1021/acs.jmedchem.9b00728. Epub, 2019 Sep 13. PMID:31483651[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||