7kh9: Difference between revisions
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<StructureSection load='7kh9' size='340' side='right'caption='[[7kh9]], [[Resolution|resolution]] 2.29Å' scene=''> | <StructureSection load='7kh9' size='340' side='right'caption='[[7kh9]], [[Resolution|resolution]] 2.29Å' scene=''> | ||
== Structural highlights == | == Structural highlights == | ||
<table><tr><td colspan='2'> | <table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7KH9 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7KH9 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]] 2.29Å</td></tr> | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">X-ray diffraction, [[Resolution|Resolution]] 2.29Å</td></tr> | ||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IM2:(5R)-5-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-[(2-{[(E)-IMINOMETHYL]AMINO}ETHYL)SULFANYL]-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>IM2</scene></td></tr> | <tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=CL:CHLORIDE+ION'>CL</scene>, <scene name='pdbligand=IM2:(5R)-5-[(1S,2R)-1-FORMYL-2-HYDROXYPROPYL]-3-[(2-{[(E)-IMINOMETHYL]AMINO}ETHYL)SULFANYL]-4,5-DIHYDRO-1H-PYRROLE-2-CARBOXYLIC+ACID'>IM2</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=7kh9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kh9 OCA], [https://pdbe.org/7kh9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kh9 RCSB], [https://www.ebi.ac.uk/pdbsum/7kh9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kh9 ProSAT]</span></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=7kh9 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7kh9 OCA], [https://pdbe.org/7kh9 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7kh9 RCSB], [https://www.ebi.ac.uk/pdbsum/7kh9 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7kh9 ProSAT]</span></td></tr> | ||
</table> | </table> | ||
<div style="background-color:#fffaf0;"> | <div style="background-color:#fffaf0;"> | ||
== Publication Abstract from PubMed == | == Publication Abstract from PubMed == | ||
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__TOC__ | __TOC__ | ||
</StructureSection> | </StructureSection> | ||
[[Category: Large Structures]] | [[Category: Large Structures]] | ||
[[Category: Hu L]] | [[Category: Hu L]] | ||
[[Category: Palzkill T]] | [[Category: Palzkill T]] | ||
[[Category: Prasad BVV]] | [[Category: Prasad BVV]] | ||
Latest revision as of 09:29, 21 November 2024
Crystal structure of OXA-48 K73A in complex with imipenemCrystal structure of OXA-48 K73A in complex with imipenem
Structural highlights
Publication Abstract from PubMedCarbapenem-hydrolyzing class D beta-lactamases (CHDLs) are an important source of resistance to these last resort beta-lactam antibiotics. OXA-48 is a member of a group of CHDLs named OXA-48-like enzymes. On the basis of sequence similarity, OXA-163 can be classified as an OXA-48-like enzyme, but it has altered substrate specificity. Compared to OXA-48, it shows impaired activity for carbapenems but displays an enhanced hydrolysis of oxyimino-cephalosporins. Here, we address the mechanistic and structural basis for carbapenem hydrolysis by OXA-48-like enzymes. Pre-steady-state kinetic analysis indicates that the rate-limiting step for OXA-48 and OXA-163 hydrolysis of carbapenems is deacylation and that the greatly reduced carbapenemase activity of OXA-163 compared to that of OXA-48 is due entirely to a slower deacylation reaction. Furthermore, our structural data indicate that the positioning of the beta5-beta6 loop is necessary for carbapenem hydrolysis by OXA-48. A major difference between the OXA-48 and OXA-163 complexes with carbapenems is that the 214-RIEP-217 deletion in OXA-163 creates a large opening in the active site that is absent in the OXA-48/carbapenem structures. We propose that the larger active site results in less constraint on the conformation of the 6alpha-hydroxyethyl group in the acyl-enzyme. The acyl-enzyme intermediate assumes multiple conformations, most of which are incompatible with rapid deacylation. Consistent with this hypothesis, molecular dynamics simulations indicate that the most stable complex is formed between OXA-48 and imipenem, which correlates with the OXA-48 hydrolysis of imipenem being the fastest observed. Furthermore, the OXA-163 complexes with imipenem and meropenem are the least stable and show significant conformational fluctuations, which correlates with the slow hydrolysis of these substrates. Mechanistic Basis of OXA-48-like beta-Lactamases' Hydrolysis of Carbapenems.,Stojanoski V, Hu L, Sankaran B, Wang F, Tao P, Prasad BVV, Palzkill T ACS Infect Dis. 2021 Jan 25. doi: 10.1021/acsinfecdis.0c00798. PMID:33492952[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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