5zft: Difference between revisions
New page: '''Unreleased structure''' The entry 5zft is ON HOLD Authors: Pan, X., Zhao, Y. Description: Crystal structure of beta-lactamase PenP mutant-E166H in complex with cephaloridine as ""pr... |
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The | ==Crystal structure of beta-lactamase PenP mutant-E166Y in complex with cephaloridine as "pre-deacylation" intermediate== | ||
<StructureSection load='5zft' size='340' side='right'caption='[[5zft]], [[Resolution|resolution]] 1.93Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[5zft]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Bacillus_licheniformis Bacillus licheniformis]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=5ZFT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=5ZFT 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]] 1.93Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CED:5-METHYL-2-[2-OXO-1-(2-THIOPHEN-2-YL-ACETYLAMINO)-ETHYL]-3,6-DIHYDRO-2H-[1,3]THIAZINE-4-CARBOXYLIC+ACID'>CED</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=5zft FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=5zft OCA], [https://pdbe.org/5zft PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=5zft RCSB], [https://www.ebi.ac.uk/pdbsum/5zft PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=5zft ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/BLAC_BACLI BLAC_BACLI] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
Serine-based beta-lactamases of Class A, C and D all rely on a key water molecule to hydrolyze and inactivate beta-lactam antibiotics. This process involves two conserved catalytic steps. In the first acylation step, the beta-lactam antibiotic forms an acyl-enzyme intermediate (ES*) with the catalytic serine residue. In the second deacylation step, an activated water molecule serves as nucleophile (WAT_Nu) to attack ES* and release the inactivated beta-lactam. The coordination and activation of WAT_Nu is not fully understood. Using time-resolved x-ray crystallography and QM/MM simulations, we analyzed three intermediate structures of Class A beta-lactamase PenP as it slowly hydrolyzed cephaloridine. WAT_Nu is centrally located in the apo structure but becomes slightly displaced away by ES* in the post-acylation structure. In the deacylation structure, WAT_Nu moves back and is positioned along the Burgi-Dunitz trajectory with favorable energetic profile to attack ES*. Unexpectedly, WAT_Nu is also found to adopt a catalytically incompetent conformation in the deacylation structure forming a hydrogen bond with ES*. Our results reveal that ES* plays a significant role in coordinating and activating WAT_Nu through subtle yet distinct interactions at different stages of the catalytic process. These interactions may serve as potential targets to circumvent beta-lactamase-mediated antibiotic resistance. | |||
The hydrolytic water molecule of Class A beta-lactamase relies on the acyl-enzyme intermediate ES* for proper coordination and catalysis.,He Y, Lei J, Pan X, Huang X, Zhao Y Sci Rep. 2020 Jun 23;10(1):10205. doi: 10.1038/s41598-020-66431-w. PMID:32576842<ref>PMID:32576842</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: Pan | <div class="pdbe-citations 5zft" style="background-color:#fffaf0;"></div> | ||
[[Category: Zhao | |||
==See Also== | |||
*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]] | |||
== References == | |||
<references/> | |||
__TOC__ | |||
</StructureSection> | |||
[[Category: Bacillus licheniformis]] | |||
[[Category: Large Structures]] | |||
[[Category: Pan X]] | |||
[[Category: Zhao Y]] | |||
Latest revision as of 11:53, 22 November 2023
Crystal structure of beta-lactamase PenP mutant-E166Y in complex with cephaloridine as "pre-deacylation" intermediateCrystal structure of beta-lactamase PenP mutant-E166Y in complex with cephaloridine as "pre-deacylation" intermediate
Structural highlights
FunctionPublication Abstract from PubMedSerine-based beta-lactamases of Class A, C and D all rely on a key water molecule to hydrolyze and inactivate beta-lactam antibiotics. This process involves two conserved catalytic steps. In the first acylation step, the beta-lactam antibiotic forms an acyl-enzyme intermediate (ES*) with the catalytic serine residue. In the second deacylation step, an activated water molecule serves as nucleophile (WAT_Nu) to attack ES* and release the inactivated beta-lactam. The coordination and activation of WAT_Nu is not fully understood. Using time-resolved x-ray crystallography and QM/MM simulations, we analyzed three intermediate structures of Class A beta-lactamase PenP as it slowly hydrolyzed cephaloridine. WAT_Nu is centrally located in the apo structure but becomes slightly displaced away by ES* in the post-acylation structure. In the deacylation structure, WAT_Nu moves back and is positioned along the Burgi-Dunitz trajectory with favorable energetic profile to attack ES*. Unexpectedly, WAT_Nu is also found to adopt a catalytically incompetent conformation in the deacylation structure forming a hydrogen bond with ES*. Our results reveal that ES* plays a significant role in coordinating and activating WAT_Nu through subtle yet distinct interactions at different stages of the catalytic process. These interactions may serve as potential targets to circumvent beta-lactamase-mediated antibiotic resistance. The hydrolytic water molecule of Class A beta-lactamase relies on the acyl-enzyme intermediate ES* for proper coordination and catalysis.,He Y, Lei J, Pan X, Huang X, Zhao Y Sci Rep. 2020 Jun 23;10(1):10205. doi: 10.1038/s41598-020-66431-w. PMID:32576842[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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