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6qw8

From Proteopedia

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Crystal structure of CTX-M-15 complexed with relebactam (16 hour soak)

Structural highlights

6qw8 is a 1 chain structure with sequence from Klebsiella pneumoniae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.1Å
Ligands:	, ,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

W1EPV7_KLEPN

Publication Abstract from PubMed

beta-Lactamase production is the major beta-lactam resistance mechanism in Gram-negative bacteria. beta-Lactamase inhibitors (BLIs) efficacious against serine beta-lactamase (SBL) producers, especially strains carrying the widely disseminated class A enzymes, are required. Relebactam, a diazabicyclooctane (DBO) BLI is in phase-3 clinical trials in combination with imipenem, for treatment of infections by multi-drug resistant Enterobacteriaceae. We show that relebactam inhibits five clinically-important class A SBLs (despite their differing spectra of activity), representing both chromosomal and plasmid-borne enzymes, i.e. the extended spectrum beta-lactamases L2 (inhibition constant 3 muM) and CTX-M-15 (21 muM); and the carbapenemases, KPC-2, -3 and -4 (1 - 5 muM). Against purified class A SBLs, relebactam is an inferior inhibitor compared to the clinically approved DBO avibactam, (9 to 120-fold differences in IC50). Minimum inhibitory concentration assays indicate relebactam potentiates beta-lactam (imipenem) activity against KPC-producing Klebsiella pneumoniae with similar potency to avibactam (with ceftazidime). Relebactam is less effective than avibactam in combination with aztreonam against Stenotrophomonas maltophilia K279a. X-ray crystal structures of relebactam bound to CTX-M-15, L2, KPC-2, KPC-3 and KPC-4 reveal its C2 linked piperidine ring can sterically clash with Asn104 (CTX-M-15) or His/Trp105 (L2 and KPCs), rationalizing its poorer inhibition activity compared to avibactam, which has a smaller C2 carboxyamide group. Mass spectrometry and crystallographic data show slow, pH-dependent relebactam desulfation by KPC-2, -3 and -4. This comprehensive comparison of relebactam binding across five clinically-important class A SBLs will inform the design of future DBOs with the aim of improving clinical efficacy of BLI:beta-lactam combinations.

Molecular Basis of Class A beta-lactamase Inhibition by Relebactam.,Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J Antimicrob Agents Chemother. 2019 Aug 5. pii: AAC.00564-19. doi:, 10.1128/AAC.00564-19. PMID:31383664^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Tooke CL, Hinchliffe P, Lang PA, Mulholland AJ, Brem J, Schofield CJ, Spencer J. Molecular Basis of Class A beta-lactamase Inhibition by Relebactam. Antimicrob Agents Chemother. 2019 Aug 5. pii: AAC.00564-19. doi:, 10.1128/AAC.00564-19. PMID:31383664 doi:http://dx.doi.org/10.1128/AAC.00564-19

1 Structural highlights
2 Function
3 Publication Abstract from PubMed
4 See Also
5 References

Proteopedia Page Contributors and Editors (what is this?)

OCA

Retrieved from "http://52.214.119.220/wiki/index.php/6qw8"

Categories: Klebsiella pneumoniae | Large Structures | Hinchliffe P | Spencer J | Tooke CL

@@ Line 3: / Line 3: @@
 <StructureSection load='6qw8' size='340' side='right'caption='[[6qw8]], [[Resolution|resolution]] 1.10&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6qw8]] is a 1 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QW8 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QW8 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6qw8]] 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=6QW8 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QW8 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MK7:(2S,5R)-1-FORMYL-N-(PIPERIDIN-4-YL)-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>MK7</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]] 1.1&#8491;</td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6qw8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qw8 OCA], [http://pdbe.org/6qw8 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qw8 RCSB], [http://www.ebi.ac.uk/pdbsum/6qw8 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qw8 ProSAT]</span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=GOL:GLYCEROL'>GOL</scene>, <scene name='pdbligand=MK7:(2S,5R)-1-FORMYL-N-(PIPERIDIN-4-YL)-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>MK7</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=6qw8 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qw8 OCA], [https://pdbe.org/6qw8 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qw8 RCSB], [https://www.ebi.ac.uk/pdbsum/6qw8 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qw8 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/W1EPV7_KLEPN W1EPV7_KLEPN]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 16: / Line 19: @@
 </div>
 <div class="pdbe-citations 6qw8" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
+[[Category: Klebsiella pneumoniae]]
 [[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: Diazabicyclooctane]]
-[[Category: Inhibitor]]
-[[Category: Relebactam]]

6qw8

From Proteopedia

Current revision

Crystal structure of CTX-M-15 complexed with relebactam (16 hour soak)

Structural highlights

Function

Publication Abstract from PubMed

See Also

References

Contents

Proteopedia Page Contributors and Editors (what is this?)

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