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==Crystal structure of NDM-1 bound to hydrolyzed meropenem representing an EI2 complex== | |||
<StructureSection load='5ypn' size='340' side='right' caption='[[5ypn]], [[Resolution|resolution]] 2.12Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5ypn]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5YPN OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5YPN FirstGlance]. <br> | |||
</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=LMP:(2~{S},3~{R},4~{S})-2-[(2~{S},3~{R})-1,3-BIS(OXIDANYL)-1-OXIDANYLIDENE-BUTAN-2-YL]-4-[(3~{S},5~{S})-5-(DIMETHYLCARBAMOYL)PYRROLIDIN-3-YL]SULFANYL-3-METHYL-3,4-DIHYDRO-2~{H}-PYRROLE-5-CARBOXYLIC+ACID'>LMP</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=5ypn FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5ypn OCA], [http://pdbe.org/5ypn PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=5ypn RCSB], [http://www.ebi.ac.uk/pdbsum/5ypn PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=5ypn ProSAT]</span></td></tr> | |||
</table> | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
New Delhi metallo-beta-lactamases (NDMs), the recent additions to metallo-beta-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of beta-lactam antibiotics and rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM-1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80-2.32 A, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme-intermediate/product derivatives, EI1, EI2, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Delta(2) to Delta(1), absence of a bridging water molecule and an exclusive beta-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the beta-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors. | |||
The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis.,Feng H, Liu X, Wang S, Fleming J, Wang DC, Liu W Nat Commun. 2017 Dec 21;8(1):2242. doi: 10.1038/s41467-017-02339-w. PMID:29269938<ref>PMID:29269938</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
<div class="pdbe-citations 5ypn" style="background-color:#fffaf0;"></div> | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Feng, H]] | |||
[[Category: Liu, W]] | [[Category: Liu, W]] | ||
[[Category: Wang, D]] | [[Category: Wang, D]] | ||
[[Category: | [[Category: Ei2 complex]] | ||
[[Category: Hydrolase]] | |||
[[Category: Mdm-1]] | |||
[[Category: Meropenem]] | |||
Revision as of 10:22, 22 February 2018
Crystal structure of NDM-1 bound to hydrolyzed meropenem representing an EI2 complexCrystal structure of NDM-1 bound to hydrolyzed meropenem representing an EI2 complex
Structural highlights
Publication Abstract from PubMedNew Delhi metallo-beta-lactamases (NDMs), the recent additions to metallo-beta-lactamases (MBLs), pose a serious public health threat due to its highly efficient hydrolysis of beta-lactam antibiotics and rapid worldwide dissemination. The MBL-hydrolyzing mechanism for carbapenems is less studied than that of penicillins and cephalosporins. Here, we report crystal structures of NDM-1 in complex with hydrolyzed imipenem and meropenem, at resolutions of 1.80-2.32 A, together with NMR spectra monitoring meropenem hydrolysis. Three enzyme-intermediate/product derivatives, EI1, EI2, and EP, are trapped in these crystals. Our structural data reveal double-bond tautomerization from Delta(2) to Delta(1), absence of a bridging water molecule and an exclusive beta-diastereomeric product, all suggesting that the hydrolytic intermediates are protonated by a bulky water molecule incoming from the beta-face. These results strongly suggest a distinct mechanism of NDM-1-catalyzed carbapenem hydrolysis from that of penicillin or cephalosporin hydrolysis, which may provide a novel rationale for design of mechanism-based inhibitors. The mechanism of NDM-1-catalyzed carbapenem hydrolysis is distinct from that of penicillin or cephalosporin hydrolysis.,Feng H, Liu X, Wang S, Fleming J, Wang DC, Liu W Nat Commun. 2017 Dec 21;8(1):2242. doi: 10.1038/s41467-017-02339-w. PMID:29269938[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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