5tg4

OXA-24/40 in Complex with Boronic Acid BA16

spinqualitylabelsall models 5tg4, resolution 1.44Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5tg4 is a 1 chain structure with sequence from Aciba. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: 3GR, BCT, JW1, MEE, SO4 NonStd Res: ABA, KCX Related: 5tg5, 5tg6, 5tg7 Gene: blaOXA-33, bla-OXA-40, blaOXA-24, blaOXA-40, oxa-24, oxa40 (ACIBA) Activity: Beta-lactamase, with EC number 3.5.2.6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Publication Abstract from PubMed beta-lactam antibiotics are crucial to the management of bacterial infections in the medical community. Due to overuse and misuse, clinically significant bacteria are now resistant to many commercially available antibiotics. The most widespread resistance mechanism to beta-lactams is the expression of beta-lactamase enzymes. To overcome beta-lactamase mediated resistance, inhibitors were designed to inactivate these enzymes. However, current inhibitors (clavulanic acid, tazobactam, and sulbactam) for beta-lactamases also contain the characteristic beta-lactam ring, making them susceptible to resistance mechanisms employed by bacteria. This presents a critical need for novel, non-beta-lactam inhibitors that can circumvent these resistance mechanisms. The carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are of particular concern, given that they efficiently hydrolyze potent carbapenem antibiotics. Unfortunately, these enzymes are not inhibited by clinically available beta-lactamase inhibitors, nor are they effectively inhibited by the newest, non-beta-lactam inhibitor, avibactam. Boronic acids are known transition state analog inhibitors of class A and C beta-lactamases, and are not extensively characterized as inhibitors of class D beta-lactamases. Importantly, boronic acids provide a novel way to potentially inhibit class D beta-lactamases. Sixteen boronic acids were selected and tested for inhibition of the CHDL OXA-24/40. Several compounds were identified as effective inhibitors of OXA-24/40, with Ki values as low as 5 muM. The X-ray crystal structures of OXA-24/40 in complex with BA3, BA4, BA8, and BA16 were determined and revealed the importance of interactions with hydrophobic residues Tyr112 and Trp115. These boronic acids serve as progenitors in optimization efforts of a novel series of inhibitors for class D beta-lactamases. This article is protected by copyright. All rights reserved. Exploring the potential of boronic acids as inhibitors of OXA-24/40 beta-lactamase.,Werner JP, Mitchell JM, Taracila MA, Bonomo RA, Powers RA Protein Sci. 2016 Dec 20. doi: 10.1002/pro.3100. PMID:27997706 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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