4LEN
CTX-M-9 in complex with the broad spectrum inhibitor 3-(2- carboxyvinyl)benzo(b)thiophene-2-boronic acid
Summary for 4LEN
| Entry DOI | 10.2210/pdb4len/pdb |
| Descriptor | Beta-lactamase, (2E)-3-[2-(dihydroxyboranyl)-1-benzothiophen-3-yl]prop-2-enoic acid (3 entities in total) |
| Functional Keywords | binding sites, structure base drug design, drug discovery, molecular, enzyme inhibitors, beta lactamases, boronic acids, broad spectrum, bacterial resistance, double perturbation cycle analysis, thermodynamics, structure activity relationship, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor |
| Biological source | Escherichia coli |
| Total number of polymer chains | 2 |
| Total formula weight | 56441.11 |
| Authors | Tondi, D. (deposition date: 2013-06-26, release date: 2014-06-18, Last modification date: 2024-10-16) |
| Primary citation | Tondi, D.,Venturelli, A.,Bonnet, R.,Pozzi, C.,Shoichet, B.K.,Costi, M.P. Targeting Class A and C Serine beta-Lactamases with a Broad-Spectrum Boronic Acid Derivative. J.Med.Chem., 57:5449-5458, 2014 Cited by PubMed Abstract: Production of β-lactamases (BLs) is the most widespread resistance mechanism adopted by bacteria to fight β-lactam antibiotics. The substrate spectrum of BLs has become increasingly broad, posing a serious health problem. Thus, there is an urgent need for novel BL inhibitors. Boronic acid transition-state analogues are able to reverse the resistance conferred by class A and C BLs. We describe a boronic acid analogue possessing interesting and potent broad-spectrum activity vs class A and C serine-based BLs. Starting from benzo(b)thiophene-2-boronic acid (BZBTH2B), a nanomolar non-β-lactam inhibitor of AmpC that can potentiate the activity of a third-generation cephalosporin against AmpC-producing resistant bacteria, we designed a novel broad-spectrum nanomolar inhibitor of class A and C BLs. Structure-based drug design (SBDD), synthesis, enzymology data, and X-ray crystallography results are discussed. We clarified the inhibitor binding geometry responsible for broad-spectrum activity vs serine-active BLs using double mutant thermodynamic cycle studies. PubMed: 24882105DOI: 10.1021/jm5006572 PDB entries with the same primary citation |
| Experimental method | X-RAY DIFFRACTION (1.5 Å) |
Structure validation
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