View source for 7zo7


==L1 metallo-beta-lactamase in complex with hydrolysed cefmetazole==
<StructureSection load='7zo7' size='340' side='right'caption='[[7zo7]], [[Resolution|resolution]] 1.63&Aring;' scene=''>
== Structural highlights ==
<table><tr><td colspan='2'>[[7zo7]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Stenotrophomonas_maltophilia Stenotrophomonas maltophilia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7ZO7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7ZO7 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]] 1.63&#8491;</td></tr>
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=JOU:(2~{R},5~{R})-2-[(1~{S})-1-[2-(cyanomethylsulfanyl)ethanoylamino]-1-methoxy-2-oxidanyl-2-oxidanylidene-ethyl]-5-[(1-methyl-1,2,3,4-tetrazol-5-yl)sulfanylmethyl]-5,6-dihydro-2~{H}-1,3-thiazine-4-carboxylic+acid'>JOU</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'>[https://proteopedia.org/fgij/fg.htm?mol=7zo7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7zo7 OCA], [https://pdbe.org/7zo7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7zo7 RCSB], [https://www.ebi.ac.uk/pdbsum/7zo7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7zo7 ProSAT]</span></td></tr>
</table>
== Function ==
[https://www.uniprot.org/uniprot/BLA1_STEMA BLA1_STEMA] Has a high activity against imipenem.
<div style="background-color:#fffaf0;">
== Publication Abstract from PubMed ==
L1 is a dizinc subclass B3 metallo-beta-lactamase (MBL) that hydrolyzes most beta-lactam antibiotics and is a key resistance determinant in the Gram-negative pathogen Stenotrophomonas maltophilia, an important cause of nosocomial infections in immunocompromised patients. L1 is not usefully inhibited by MBL inhibitors in clinical trials, underlying the need for further studies on L1 structure and mechanism. We describe kinetic studies and crystal structures of L1 in complex with hydrolyzed beta-lactams from the penam (mecillinam), cephem (cefoxitin/cefmetazole), and carbapenem (tebipenem, doripenem, and panipenem) classes. Despite differences in their structures, all the beta-lactam-derived products hydrogen bond to Tyr33, Ser221, and Ser225 and are stabilized by interactions with a conserved hydrophobic pocket. The carbapenem products were modeled as Delta(1)-imines, with (2S)-stereochemistry. Their binding mode is determined by the presence of a 1beta-methyl substituent: the Zn-bridging hydroxide either interacts with the C-6 hydroxyethyl group (1beta-hydrogen-containing carbapenems) or is displaced by the C-6 carboxylate (1beta-methyl-containing carbapenems). Unexpectedly, the mecillinam product is a rearranged N-formyl amide rather than penicilloic acid, with the N-formyl oxygen interacting with the Zn-bridging hydroxide. NMR studies imply mecillinam rearrangement can occur nonenzymatically in solution. Cephem-derived imine products are bound with (3R)-stereochemistry and retain their 3' leaving groups, likely representing stable endpoints, rather than intermediates, in MBL-catalyzed hydrolysis. Our structures show preferential complex formation by carbapenem- and cephem-derived species protonated on the equivalent (beta) faces and so identify interactions that stabilize diverse hydrolyzed antibiotics. These results may be exploited in developing antibiotics, and beta-lactamase inhibitors, that form long-lasting complexes with dizinc MBLs.

Interactions of hydrolyzed beta-lactams with the L1 metallo-beta-lactamase: Crystallography supports stereoselective binding of cephem/carbapenem products.,Hinchliffe P, Calvopina K, Rabe P, Mojica MF, Schofield CJ, Dmitrienko GI, Bonomo RA, Vila AJ, Spencer J J Biol Chem. 2023 May;299(5):104606. doi: 10.1016/j.jbc.2023.104606. Epub 2023 , Mar 15. PMID:36924941<ref>PMID:36924941</ref>

From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
</div>
<div class="pdbe-citations 7zo7" style="background-color:#fffaf0;"></div>
== References ==
<references/>
__TOC__
</StructureSection>
[[Category: Large Structures]]
[[Category: Stenotrophomonas maltophilia]]
[[Category: Hinchliffe P]]
[[Category: Spencer J]]