6qw7

From Proteopedia

(Difference between revisions)

Current revision

Crystal structure of L2 complexed with relebactam (16 hour soak)

Structural highlights

6qw7 is a 2 chain structure with sequence from Stenotrophomonas maltophilia. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:	X-ray diffraction, Resolution 1.78Å
Ligands:	,
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

Q9RBQ1_STEMA

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/6qw7"

Categories: Large Structures | Stenotrophomonas maltophilia | Hinchliffe P | Spencer J | Tooke CL

@@ Line 3: / Line 3: @@
 <StructureSection load='6qw7' size='340' side='right'caption='[[6qw7]], [[Resolution|resolution]] 1.78&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[6qw7]] is a 2 chain structure. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QW7 OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6QW7 FirstGlance]. <br>
+<table><tr><td colspan='2'>[[6qw7]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Stenotrophomonas_maltophilia Stenotrophomonas maltophilia]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=6QW7 OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=6QW7 FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <scene name='pdbligand=MK7:(2S,5R)-1-FORMYL-N-(PIPERIDIN-4-YL)-5-[(SULFOOXY)AMINO]PIPERIDINE-2-CARBOXAMIDE'>MK7</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]] 1.78&#8491;</td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Beta-lactamase Beta-lactamase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=3.5.2.6 3.5.2.6] </span></td></tr>
+<tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=DSN:D-SERINE'>DSN</scene>, <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'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=6qw7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qw7 OCA], [http://pdbe.org/6qw7 PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=6qw7 RCSB], [http://www.ebi.ac.uk/pdbsum/6qw7 PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=6qw7 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=6qw7 FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=6qw7 OCA], [https://pdbe.org/6qw7 PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=6qw7 RCSB], [https://www.ebi.ac.uk/pdbsum/6qw7 PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=6qw7 ProSAT]</span></td></tr>
 </table>
+== Function ==
+[https://www.uniprot.org/uniprot/Q9RBQ1_STEMA Q9RBQ1_STEMA]
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 17: / Line 19: @@
 </div>
 <div class="pdbe-citations 6qw7" style="background-color:#fffaf0;"></div>
+==See Also==
+*[[Beta-lactamase 3D structures|Beta-lactamase 3D structures]]
 == References ==
 <references/>
 __TOC__
 </StructureSection>
-[[Category: Beta-lactamase]]
 [[Category: Large Structures]]
-[[Category: Hinchliffe, P]]
+[[Category: Stenotrophomonas maltophilia]]
-[[Category: Spencer, J]]
+[[Category: Hinchliffe P]]
-[[Category: Tooke, C L]]
+[[Category: Spencer J]]
-[[Category: Antibiotic resistance]]
+[[Category: Tooke CL]]
-[[Category: Antimicrobial protein]]
-[[Category: Diazabicyclooctane]]
-[[Category: Inhibitor]]
-[[Category: Relebactam]]

6qw7

From Proteopedia

Current revision

Crystal structure of L2 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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