7qq5 - Revision history

OCA at 13:21, 1 February 2024

2024-02-01T13:21:05Z

←Older revision		Revision as of 13:21, 1 February 2024
Line 4:		Line 4:
	== Structural highlights ==		== Structural highlights ==
	<table><tr><td colspan='2'>[[7qq5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae_IS53 Klebsiella pneumoniae IS53]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 FirstGlance]. <br>		<table><tr><td colspan='2'>[[7qq5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae_IS53 Klebsiella pneumoniae IS53]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 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=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></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]] 0.95Å</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=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 ProSAT]</span></td></tr>
	</table>		</table>
	== Function ==		== Function ==
-	[[https://www.uniprot.org/uniprot/W1EPV7_KLEPN W1EPV7_KLEPN]]	+	[https://www.uniprot.org/uniprot/W1EPV7_KLEPN W1EPV7_KLEPN]
		+
		+	==See Also==
		+	*[[Beta-lactamase 3D structures\|Beta-lactamase 3D structures]]
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>

OCA at 07:20, 8 September 2022

2022-09-08T07:20:12Z

←Older revision		Revision as of 07:20, 8 September 2022
Line 3:		Line 3:
	<StructureSection load='7qq5' size='340' side='right'caption='[[7qq5]], [[Resolution\|resolution]] 0.95Å' scene=''>		<StructureSection load='7qq5' size='340' side='right'caption='[[7qq5]], [[Resolution\|resolution]] 0.95Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>[[7qq5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7qq5]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Klebsiella_pneumoniae_IS53 Klebsiella pneumoniae IS53]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 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=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=SO4:SULFATE+ION'>SO4</scene></td></tr>
-	~~<tr id='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat">~~<scene name='pdbligand=DSN:D-SERINE'>DSN</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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 ProSAT]</span></td></tr>
	</table>		</table>
-	~~<div style~~=~~"background-color:#fffaf0;">~~	+	== Function ==
-	=~~= Publication Abstract from PubMed~~ ==	+	[[https://www.uniprot.org/uniprot/W1EPV7_KLEPN W1EPV7_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®/PubMed®, a database of the U~~.S. ~~National Library of Medicine.<br>~~	+
-	</~~div>~~	+
-	~~<div class="pdbe-citations 7qq5" style="background-color:#fffaf0;"></div>~~	+
-	~~== References ==~~	+
-	~~<references~~/>	+
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
-	[[Category: ~~Beta-lactamase~~]]	+	[[Category: Klebsiella pneumoniae IS53]]
	[[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: Cross-link]]~~	+
-	~~[[Category: Inhibitor~~]]	+

OCA at 16:23, 6 July 2022

2022-07-06T16:23:28Z

←Older revision		Revision as of 16:23, 6 July 2022
Line 1:		Line 1:

	==Structure of CTX-M-15 K73A mutant crystallised in the presence of enmetazobactam (AAI101)==		==Structure of CTX-M-15 K73A mutant crystallised in the presence of enmetazobactam (AAI101)==
-	<StructureSection load='7qq5' size='340' side='right'caption='[[7qq5]]' scene=''>	+	<StructureSection load='7qq5' size='340' side='right'caption='[[7qq5]], [[Resolution\|resolution]] 0.95Å' scene=''>
	== Structural highlights ==		== Structural highlights ==
-	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 FirstGlance]. <br>	+	<table><tr><td colspan='2'>[[7qq5]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 FirstGlance]. <br>
-	</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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 ProSAT]</span></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='NonStdRes'><td class="sblockLbl"><b>[[Non-Standard_Residue\|NonStd Res:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 ProSAT]</span></td></tr>
	</table>		</table>
		+	<div style="background-color:#fffaf0;">
		+	== Publication Abstract from PubMed ==
		+	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®/PubMed®, a database of the U.S. National Library of Medicine.<br>
		+	</div>
		+	<div class="pdbe-citations 7qq5" style="background-color:#fffaf0;"></div>
		+	== References ==
		+	<references/>
	__TOC__		__TOC__
	</StructureSection>		</StructureSection>
		+	[[Category: Beta-lactamase]]
	[[Category: Large Structures]]		[[Category: Large Structures]]
-	[[Category: Hinchliffe P]]	+	[[Category: Hinchliffe, P]]
-	[[Category: Spencer J]]	+	[[Category: Spencer, J]]
-	[[Category: Tooke CL]]	+	[[Category: Tooke, C L]]
		+	[[Category: Antibiotic resistance]]
		+	[[Category: Antimicrobial protein]]
		+	[[Category: Cross-link]]
		+	[[Category: Inhibitor]]

OCA at 07:58, 25 May 2022

2022-05-25T07:58:03Z

←Older revision		Revision as of 07:58, 25 May 2022
Line 1:		Line 1:
-	'''Unreleased structure'''

-	~~The entry~~ 7qq5 is ~~ON HOLD until Paper Publication~~	+	==Structure of CTX-M-15 K73A mutant crystallised in the presence of enmetazobactam (AAI101)==
-		+	<StructureSection load='7qq5' size='340' side='right'caption='[[7qq5]]' scene=''>
-	~~Authors~~:	+	== Structural highlights ==
-		+	<table><tr><td colspan='2'>Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=7QQ5 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=7QQ5 FirstGlance]. <br>
-	~~Description~~:	+	</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=7qq5 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=7qq5 OCA], [https://pdbe.org/7qq5 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=7qq5 RCSB], [https://www.ebi.ac.uk/pdbsum/7qq5 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=7qq5 ProSAT]</span></td></tr>
-	[[Category: ~~Unreleased Structures~~]]	+	</table>
		+	__TOC__
		+	</StructureSection>
		+	[[Category: Large Structures]]
		+	[[Category: Hinchliffe P]]
		+	[[Category: Spencer J]]
		+	[[Category: Tooke CL]]

OCA at 05:18, 27 January 2022

2022-01-27T05:18:02Z

←Older revision		Revision as of 05:18, 27 January 2022
Line 1:		Line 1:
	'''Unreleased structure'''		'''Unreleased structure'''

-	The entry 7qq5 is ON HOLD	+	The entry 7qq5 is ON HOLD until Paper Publication

	Authors:		Authors:

OCA: Protected "7qq5" [edit=sysop:move=sysop]

2022-01-12T08:32:35Z

Protected "7qq5" [edit=sysop:move=sysop]

←Older revision

Revision as of 08:32, 12 January 2022

OCA: New page: '''Unreleased structure''' The entry 7qq5 is ON HOLD Authors: Description: Category: Unreleased Structures

2022-01-12T08:32:34Z

New page: '''Unreleased structure''' The entry 7qq5 is ON HOLD Authors: Description: Category: Unreleased Structures

New page

'''Unreleased structure'''

The entry 7qq5 is ON HOLD

Authors:

Description:
[[Category: Unreleased Structures]]