We apologize for Proteopedia being slow to respond. For the past two years, a new implementation of Proteopedia has been being built. Soon, it will replace this 18-year old system. All existing content will be moved to the new system at a date that will be announced here.

7r3r

From Proteopedia

(Difference between revisions)
Jump to: navigation, search
Line 3: Line 3:
<StructureSection load='7r3r' size='340' side='right'caption='[[7r3r]], [[Resolution|resolution]] 1.17&Aring;' scene=''>
<StructureSection load='7r3r' size='340' side='right'caption='[[7r3r]], [[Resolution|resolution]] 1.17&Aring;' scene=''>
== Structural highlights ==
== Structural highlights ==
-
<table><tr><td colspan='2'>[[7r3r]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7R3R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R3R FirstGlance]. <br>
+
<table><tr><td colspan='2'>[[7r3r]] 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=7R3R OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7R3R FirstGlance]. <br>
</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=SO4:SULFATE+ION'>SO4</scene></td></tr>
</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=SO4:SULFATE+ION'>SO4</scene></td></tr>
-
<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[https://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [https://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </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=7r3r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r3r OCA], [https://pdbe.org/7r3r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r3r RCSB], [https://www.ebi.ac.uk/pdbsum/7r3r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r3r 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=7r3r FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7r3r OCA], [https://pdbe.org/7r3r PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7r3r RCSB], [https://www.ebi.ac.uk/pdbsum/7r3r PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7r3r ProSAT]</span></td></tr>
</table>
</table>
-
<div style="background-color:#fffaf0;">
+
== Function ==
-
== Publication Abstract from PubMed ==
+
[[https://www.uniprot.org/uniprot/G3G192_KLEPN G3G192_KLEPN]]
-
beta-Lactamases hydrolyze beta-lactam antibiotics and are major determinants of antibiotic resistance in Gram-negative pathogens. Enmetazobactam (formerly AAI101) and tazobactam are penicillanic acid sulfone (PAS) beta-lactamase inhibitors that differ by an additional methyl group on the triazole ring of enmetazobactam, rendering it zwitterionic. In this study, ultrahigh-resolution X-ray crystal structures and mass spectrometry revealed the mechanism of PAS inhibition of CTX-M-15, an extended-spectrum beta-lactamase (ESBL) globally disseminated among Enterobacterales. CTX-M-15 crystals grown in the presence of enmetazobactam or tazobactam revealed loss of the Ser70 hydroxyl group and formation of a lysinoalanine cross-link between Lys73 and Ser70, two residues critical for catalysis. Moreover, the residue at position 70 undergoes epimerization, resulting in formation of a d-amino acid. Cocrystallization of enmetazobactam or tazobactam with CTX-M-15 with a Glu166Gln mutant revealed the same cross-link, indicating that this modification is not dependent on Glu166-catalyzed deacylation of the PAS-acylenzyme. A cocrystal structure of enmetazobactam with CTX-M-15 with a Lys73Ala mutation indicates that epimerization can occur without cross-link formation and positions the Ser70 Cbeta closer to Lys73, likely facilitating formation of the Ser70-Lys73 cross-link. A crystal structure of a tazobactam-derived imine intermediate covalently linked to Ser70, obtained after 30 min of exposure of CTX-M-15 crystals to tazobactam, supports formation of an initial acylenzyme by PAS inhibitors on reaction with CTX-M-15. These data rationalize earlier results showing CTX-M-15 deactivation by PAS inhibitors to involve loss of protein mass, and they identify a distinct mechanism of beta-lactamase inhibition by these agents. IMPORTANCE beta-Lactams are the most prescribed antibiotic class for treating bacterial diseases, but their continued efficacy is threatened by bacterial strains producing beta-lactamase enzymes that catalyze their inactivation. The CTX-M family of ESBLs are major contributors to beta-lactam resistance in Enterobacterales, preventing effective treatment with most penicillins and cephalosporins. Combining beta-lactams with beta-lactamase inhibitors (BLIs) is a validated route to overcome such resistance. Here, we describe how exposure to enmetazobactam and tazobactam, BLIs based on a penicillanic acid sulfone (PAS) scaffold, leads to a protein modification in CTX-M-15, resulting in irremediable inactivation of this most commonly encountered member of the CTX-M family. High-resolution X-ray crystal structures showed that PAS exposure induces formation of a cross-link between Ser70 and Lys73, two residues critical to beta-lactamase function. This previously undescribed mechanism of inhibition furthers our understanding of beta-lactamase inhibition by classical PAS inhibitors and provides a basis for further, rational inhibitor development.
+
-
 
+
-
Penicillanic Acid Sulfones Inactivate the Extended-Spectrum beta-Lactamase CTX-M-15 through Formation of a Serine-Lysine Cross-Link: an Alternative Mechanism of beta-Lactamase Inhibition.,Hinchliffe P, Tooke CL, Bethel CR, Wang B, Arthur C, Heesom KJ, Shapiro S, Schlatzer DM, Papp-Wallace KM, Bonomo RA, Spencer J mBio. 2022 Jun 28;13(3):e0179321. doi: 10.1128/mbio.01793-21. Epub 2022 May 25. PMID:35612361<ref>PMID:35612361</ref>
+
-
 
+
-
From MEDLINE&reg;/PubMed&reg;, a database of the U.S. National Library of Medicine.<br>
+
-
</div>
+
-
<div class="pdbe-citations 7r3r" style="background-color:#fffaf0;"></div>
+
-
== References ==
+
-
<references/>
+
__TOC__
__TOC__
</StructureSection>
</StructureSection>
-
[[Category: Beta-lactamase]]
+
[[Category: Klebsiella pneumoniae]]
[[Category: Large Structures]]
[[Category: Large Structures]]
-
[[Category: Hinchliffe, P]]
+
[[Category: Hinchliffe P]]
-
[[Category: Spencer, J]]
+
[[Category: Spencer J]]
-
[[Category: Tooke, C L]]
+
[[Category: Tooke CL]]
-
[[Category: Antibiotic resistance]]
+
-
[[Category: Antimicrobial protein]]
+
-
[[Category: Disulfide]]
+
-
[[Category: Inhibitor]]
+

Revision as of 07:20, 8 September 2022

Crystal structure of CTX-M-15 G238C mutant apoenzyme

PDB ID 7r3r

Drag the structure with the mouse to rotate

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/7r3r"
Personal tools