View source for 6mdu


==Crystal structure of NDM-1 with compound 7==
<StructureSection load='6mdu' size='340' side='right'caption='[[6mdu]], [[Resolution|resolution]] 1.15&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[6mdu]] 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=6MDU OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6MDU 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]] 1.15&#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=N1G:1,5-diphenyl-N-(1H-tetrazol-5-yl)-1H-pyrazole-3-carboxamide'>N1G</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=6mdu FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6mdu OCA], [https://pdbe.org/6mdu PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6mdu RCSB], [https://www.ebi.ac.uk/pdbsum/6mdu PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6mdu 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 ==
Serine and metallo-carbapenemases are a serious health concern due to their capability to hydrolyze nearly all beta-lactam antibiotics. However, the molecular basis for their unique broad-spectrum substrate profile is poorly understood, particularly for serine carbapenemases, such as KPC-2. Using substrates and newly identified small molecules, we compared the ligand binding properties of KPC-2 with the noncarbapenemase CTX-M-14, both of which are Class A beta-lactamases with highly similar active sites. Notably, compared to CTX-M-14, KPC-2 was more potently inhibited by hydrolyzed beta-lactam products (product inhibition), as well as by a series of novel tetrazole-based inhibitors selected from molecular docking against CTX-M-14. Together with complex crystal structures, these data suggest that the KPC-2 active site has an enhanced ability to form favorable interactions with substrates and small molecule ligands due to its increased hydrophobicity and flexibility. Such properties are even more pronounced in metallo-carbapenemases, such as NDM-1, which was also inhibited by some of the novel tetrazole compounds, including one displaying comparable low muM affinities against both KPC-2 and NDM-1. Our results suggest that carbapenemase activity confers an evolutionary advantage on producers via a broad beta-lactam substrate scope but also a mechanistic Achilles' heel that can be exploited for new inhibitor discovery. The complex structures demonstrate, for the first time, how noncovalent inhibitors can be engineered to simultaneously target both serine and metallo-carbapenemases. Despite the relatively modest activity of the current compounds, these studies also demonstrate that hydrolyzed products and tetrazole-based chemotypes can provide valuable starting points for broad-spectrum inhibitor discovery against carbapenemases.

Active-Site Druggability of Carbapenemases and Broad-Spectrum Inhibitor Discovery.,Torelli NJ, Akhtar A, DeFrees K, Jaishankar P, Pemberton OA, Zhang X, Johnson C, Renslo AR, Chen Y ACS Infect Dis. 2019 Apr 15. doi: 10.1021/acsinfecdis.9b00052. PMID:30942078<ref>PMID:30942078</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 6mdu" 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: Akhtar A]]
[[Category: Chen Y]]