4df6

Crystal Structure of the inhibitor NXL104 Covalent Adduct with TB B-lactamase

spinqualitylabelsall models 4df6, resolution 2.29Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4df6 is a 1 chain structure with sequence from Mycobacterium tuberculosis. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.29Å Ligands: NXL, PO4 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function BLAC_MYCTU Publication Abstract from PubMed NXL104 is a novel beta-lactamase inhibitor with a non-lactam structural scaffold. Our kinetic and mass spectrometric analysis demonstrates that NXL104 quantitatively inhibits BlaC, the only chromosomally encoded beta-lactamase from Mycobacterium tuberculosis, by forming a carbamyl adduct with the enzyme. The inhibition efficiency (k(2)/K) of NXL104 was shown to be more than 100-fold lower than that of clavulanate, a classical beta-lactamase inhibitor, which is probably caused by the bulky rings of NXL104. However, the decarbamylation rate constant (k(3)) was determined to be close to zero. The BlaC-NXL104 adduct remained stable for at least 48 h, while the hydrolysis of the BlaC-clavulanate adduct was observed after 2 days. The three-dimensional crystal structure of the BlaC--NXL104 carbamyl adduct was determined at a resolution of 2.3 A. Interestingly, the sulfate group of NXL104 occupies the position of a phosphate ion in the structure of the BlaC-clavulanate adduct and is hydrogen bonded to residues Ser128, Thr237, and Thr239. Favorable interactions are also seen in the electrostatic potential map. We propose that these additional interactions, as well as the intrinsic stability of the carbamyl linkage, contribute to the extraordinary stability of the BlaC-NXL104 adduct. NXL104 Irreversibly Inhibits the beta-Lactamase from Mycobacterium tuberculosis.,Xu H, Hazra S, Blanchard JS Biochemistry. 2012 May 22. PMID:22587688 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-lactamase 3D structures

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