6d19: Difference between revisions

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~~'''Unreleased structure'''~~

~~The entry~~ 6d19 is ~~ON HOLD~~

==Crystal structure of KPC-2 complexed with compound 9==

== Structural highlights ==

<table><tr><td colspan='2'>[[6d19]] is a 1 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=6D19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D19 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]] 1.45Å</td></tr>

<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=YKG:(5-bromanyl-7-methyl-2-oxidanylidene-chromen-4-yl)methylphosphonic+acid'>YKG</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=6d19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d19 OCA], [https://pdbe.org/6d19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d19 RCSB], [https://www.ebi.ac.uk/pdbsum/6d19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d19 ProSAT]</span></td></tr>

</table>

== Function ==

[https://www.uniprot.org/uniprot/BLKPC_KLEPN BLKPC_KLEPN] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency.

== Publication Abstract from PubMed ==

Gram-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.

~~Authors~~:

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<ref>PMID:31483651</ref>

~~Description~~:

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br>

[[Category: ~~Unreleased~~ Structures]]

</div>

==See Also==

*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]

== References ==

__TOC__

</StructureSection>

[[Category: Klebsiella pneumoniae]]

[[Category: Large Structures]]

[[Category: Chen Y]]

[[Category: Pemberton OA]]

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@@ Line 1: / Line 1: @@
-'''Unreleased structure'''
-The entry 6d19 is ON HOLD
+==Crystal structure of KPC-2 complexed with compound 9==
+<StructureSection load='6d19' size='340' side='right'caption='[[6d19]], [[Resolution|resolution]] 1.45&Aring;' scene=''>
+== Structural highlights ==
+<table><tr><td colspan='2'>[[6d19]] is a 1 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=6D19 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6D19 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]] 1.45&#8491;</td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=YKG:(5-bromanyl-7-methyl-2-oxidanylidene-chromen-4-yl)methylphosphonic+acid'>YKG</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=6d19 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6d19 OCA], [https://pdbe.org/6d19 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6d19 RCSB], [https://www.ebi.ac.uk/pdbsum/6d19 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6d19 ProSAT]</span></td></tr>
+</table>
+== Function ==
+[https://www.uniprot.org/uniprot/BLKPC_KLEPN BLKPC_KLEPN] Hydrolyzes carbapenems, penicillins, cephalosporins and monobactams with varying efficiency.
+<div style="background-color:#fffaf0;">
+== Publication Abstract from PubMed ==
+Gram-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.
-Authors:
+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<ref>PMID:31483651</ref>
-Description:
+From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
-[[Category: Unreleased Structures]]
+</div>
+<div class="pdbe-citations 6d19" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
+== References ==
+<references/>
+__TOC__
+</StructureSection>
+[[Category: Klebsiella pneumoniae]]
+[[Category: Large Structures]]
+[[Category: Chen Y]]
+[[Category: Pemberton OA]]