5w14 | pdb_00005w14

ADC-7 in complex with boronic acid transition state inhibitor S03043

spinqualitylabelsall models 5w14, resolution 1.88Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 5w14 is a 4 chain structure with sequence from Acinetobacter baumannii. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 1.88Å Ligands: 9TJ Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function Q6DRA1_ACIBA Publication Abstract from PubMed Boronic acids are attracting a lot of attention as -lactamase inhibitors, and in particular compound S02030 (Ki = 44 nM) proved to be a good lead compound against ADC-7 (Acinetobacter Derived Cephalosporinase), one of the most significant resistance determinants in A. baumannii. The atomic structure of the ADC-7/S02030 complex highlighted the importance of critical structural determinants for recognition of the boronic acids. Herein, to elucidate the role in recognition of the R2-carboxylate, which mimics the C3/C4 found in -lactams, we designed, synthesized, and characterized six derivatives of S02030 (3a). Out of the six compounds, the best inhibitors proved to be those with an explicit negative charge (compounds 3a-c and 3h,j, Ki = 44-115 nM), which is in contrast to the derivatives where the negative charge is omitted, such as the amide derivative 3d (Ki = 224 nM) and the hydroxyamide derivative 3e (Ki = 155 nM). To develop a structural characterization of inhibitor binding in the active site, the X-ray crystal structures of ADC-7 in a complex with compounds 3c, SM23, and EC04 were determined. All three compounds share the same structural features as in S02030, but only differ in the carboxy-R2 side chain, thereby providing the opportunity of exploring the distinct binding mode of the negatively charged R2 side chain. This cephalosporiase demonstrates a high degree of versatility in recognition, employing different residues to directly interact with the carboxylate, thus suggesting the existence of a "carboxylate binding region" rather than binding site in ADC enzymes. Furthermore, this class of compounds was tested against resistant clinical strains of A. baumannii and are effective at inhibiting bacterial growth in conjunction with a -lactam antibiotic. Inhibition of Acinetobacter-Derived Cephalosporinase (ADC): Exploring the Carboxylate Recognition Site Using Novel beta-Lactamase Inhibitors.,Caselli E, Romagnoli C, Powers RA, Taracila MA, Bouza AA, Swanson HC, Smolen KA, Fini F, Wallar BJ, Bonomo RA, Prati F ACS Infect Dis. 2017 Nov 16. doi: 10.1021/acsinfecdis.7b00153. PMID:29144725 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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