8ehh: Difference between revisions
m Protected "8ehh" [edit=sysop:move=sysop] |
No edit summary |
||
| (2 intermediate revisions by the same user not shown) | |||
| Line 1: | Line 1: | ||
The | ==Crystal structure of the class A extended-spectrum beta-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolution== | ||
<StructureSection load='8ehh' size='340' side='right'caption='[[8ehh]], [[Resolution|resolution]] 1.03Å' scene=''> | |||
== Structural highlights == | |||
<table><tr><td colspan='2'>[[8ehh]] 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=8EHH OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=8EHH 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]] 1.03Å</td></tr> | |||
<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=MK7:(2S,5R)-1-FORMYL-N-(PIPERIDIN-4-YL)-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>MK7</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=8ehh FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=8ehh OCA], [https://pdbe.org/8ehh PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=8ehh RCSB], [https://www.ebi.ac.uk/pdbsum/8ehh PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=8ehh ProSAT]</span></td></tr> | |||
</table> | |||
== Function == | |||
[https://www.uniprot.org/uniprot/Q6ZXB6_KLEPN Q6ZXB6_KLEPN] | |||
<div style="background-color:#fffaf0;"> | |||
== Publication Abstract from PubMed == | |||
The use of beta-lactam/beta-lactamase inhibitors constitutes an important strategy to counteract beta-lactamases in multidrug-resistant (MDR) Gram-negative bacteria. Recent reports have described ceftazidime-/avibactam-resistant isolates producing CTX-M variants with different amino acid substitutions (e.g., P167S, L169Q, and S130G). Relebactam (REL) combined with imipenem has proved very effective against Enterobacterales producing ESBLs, serine-carbapenemases, and AmpCs. Herein, we evaluated the inhibitory efficacy of REL against CTX-M-96, a CTX-M-15-type variant. The CTX-M-96 structure was obtained in complex with REL at 1.03 A resolution (PDB 8EHH). REL was covalently bound to the S70-Ogamma atom upon cleavage of the C7-N6 bond. Compared with apo CTX-M-96, binding of REL forces a slight displacement of the deacylating water inwards the active site (0.81 A), making the E166 and N170 side chains shift to create a proper hydrogen bonding network. Binding of REL also disturbs the hydrophobic patch formed by Y105, P107, and Y129, likely due to the piperidine ring of REL that creates clashes with these residues. Also, a remarkable change in the positioning of the N104 sidechain is also affected by the piperidine ring. Therefore, differences in the kinetic behavior of REL against class A beta-lactamases seem to rely, at least in part, on differences in the residues being involved in the association and stabilization of the inhibitor before hydrolysis. Our data provide the biochemical and structural basis for REL effectiveness against CTX-M-producing Gram-negative pathogens and essential details for further DBO design. Imipenem/REL remains an important choice for dealing with isolates co-producing CTX-M with other beta-lactamases. | |||
Crystal structure of the class A extended-spectrum beta-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolution.,Ghiglione B, Rodriguez MM, Penzotti P, Bethel CR, Gutkind G, Bonomo RA, Klinke S, Power P Antimicrob Agents Chemother. 2024 Aug 7;68(8):e0172123. doi: , 10.1128/aac.01721-23. Epub 2024 Jul 11. PMID:38990013<ref>PMID:38990013</ref> | |||
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> | |||
[[Category: | </div> | ||
[[Category: | <div class="pdbe-citations 8ehh" style="background-color:#fffaf0;"></div> | ||
[[Category: Bonomo | == References == | ||
[[Category: | <references/> | ||
[[Category: | __TOC__ | ||
[[Category: | </StructureSection> | ||
[[Category: Power | [[Category: Klebsiella pneumoniae]] | ||
[[Category: Large Structures]] | |||
[[Category: Bonomo RA]] | |||
[[Category: Ghiglione B]] | |||
[[Category: Gutkind G]] | |||
[[Category: Klinke S]] | |||
[[Category: Power P]] | |||
[[Category: Rodriguez MM]] | |||
Latest revision as of 12:50, 9 October 2024
Crystal structure of the class A extended-spectrum beta-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolutionCrystal structure of the class A extended-spectrum beta-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolution
Structural highlights
FunctionPublication Abstract from PubMedThe use of beta-lactam/beta-lactamase inhibitors constitutes an important strategy to counteract beta-lactamases in multidrug-resistant (MDR) Gram-negative bacteria. Recent reports have described ceftazidime-/avibactam-resistant isolates producing CTX-M variants with different amino acid substitutions (e.g., P167S, L169Q, and S130G). Relebactam (REL) combined with imipenem has proved very effective against Enterobacterales producing ESBLs, serine-carbapenemases, and AmpCs. Herein, we evaluated the inhibitory efficacy of REL against CTX-M-96, a CTX-M-15-type variant. The CTX-M-96 structure was obtained in complex with REL at 1.03 A resolution (PDB 8EHH). REL was covalently bound to the S70-Ogamma atom upon cleavage of the C7-N6 bond. Compared with apo CTX-M-96, binding of REL forces a slight displacement of the deacylating water inwards the active site (0.81 A), making the E166 and N170 side chains shift to create a proper hydrogen bonding network. Binding of REL also disturbs the hydrophobic patch formed by Y105, P107, and Y129, likely due to the piperidine ring of REL that creates clashes with these residues. Also, a remarkable change in the positioning of the N104 sidechain is also affected by the piperidine ring. Therefore, differences in the kinetic behavior of REL against class A beta-lactamases seem to rely, at least in part, on differences in the residues being involved in the association and stabilization of the inhibitor before hydrolysis. Our data provide the biochemical and structural basis for REL effectiveness against CTX-M-producing Gram-negative pathogens and essential details for further DBO design. Imipenem/REL remains an important choice for dealing with isolates co-producing CTX-M with other beta-lactamases. Crystal structure of the class A extended-spectrum beta-lactamase CTX-M-96 in complex with relebactam at 1.03 Angstrom resolution.,Ghiglione B, Rodriguez MM, Penzotti P, Bethel CR, Gutkind G, Bonomo RA, Klinke S, Power P Antimicrob Agents Chemother. 2024 Aug 7;68(8):e0172123. doi: , 10.1128/aac.01721-23. Epub 2024 Jul 11. PMID:38990013[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
|
| ||||||||||||||||||