3gs6

Vibrio Cholerea family 3 glycoside hydrolase (NagZ)in complex with N-butyryl-PUGNAc

spinqualitylabelsall models 3gs6, resolution 2.30Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3gs6 is a 1 chain structure with sequence from Vibrio cholerae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.3Å Ligands: GOL, NP6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function NAGZ_VIBCH Plays a role in peptidoglycan recycling by cleaving the terminal beta-1,4-linked N-acetylglucosamine (GlcNAc) from peptide-linked peptidoglycan fragments, giving rise to free GlcNAc, anhydro-N-acetylmuramic acid and anhydro-N-acetylmuramic acid-linked peptides. Plays a role in beta-lactam antibiotic resistance via its role in generating anhydro-N-acetylmuramic acid-linked peptides; these peptides function as signaling molecules that induce high-level expression of the beta-lactamase AmpC. Evolutionary Conservation Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf. Publication Abstract from PubMed NagZ is an exo-N-acetyl-beta-glucosaminidase, found within Gram-negative bacteria, that acts in the peptidoglycan recycling pathway to cleave N-acetylglucosamine residues off peptidoglycan fragments. This activity is required for resistance to cephalosporins mediated by inducible AmpC beta-lactamase. NagZ uses a catalytic mechanism involving a covalent glycosyl enzyme intermediate, unlike that of the human exo-N-acetyl-beta-glucosaminidases: O-GlcNAcase and the beta-hexosaminidase isoenzymes. These latter enzymes, which remove GlcNAc from glycoconjugates, use a neighboring-group catalytic mechanism that proceeds through an oxazoline intermediate. Exploiting these mechanistic differences we previously developed 2-N-acyl derivatives of O-(2-acetamido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc), which selectively inhibits NagZ over the functionally related human enzymes and attenuate antibiotic resistance in Gram-negatives that harbor inducible AmpC. To understand the structural basis for the selectivity of these inhibitors for NagZ, we have determined its crystallographic structure in complex with N-valeryl-PUGNAc, the most selective known inhibitor of NagZ over both the human beta-hexosaminidases and O-GlcNAcase. The selectivity stems from the five-carbon acyl chain of N-valeryl-PUGNAc, which we found ordered within the enzyme active site. In contrast, a structure determination of a human O-GlcNAcase homologue bound to a related inhibitor N-butyryl-PUGNAc, which bears a four-carbon chain and is selective for both NagZ and O-GlcNAcase over the human beta-hexosamnidases, reveals that this inhibitor induces several conformational changes in the active site of this O-GlcNAcase homologue. A comparison of these complexes, and with the human beta-hexosaminidases, reveals how selectivity for NagZ can be engineered by altering the 2-N-acyl substituent of PUGNAc to develop inhibitors that repress AmpC mediated beta-lactam resistance. Insight into a strategy for attenuating AmpC-mediated beta-lactam resistance: Structural basis for selective inhibition of the glycoside hydrolase NagZ.,Balcewich MD, Stubbs KA, He Y, James TW, Davies GJ, Vocadlo DJ, Mark BL Protein Sci. 2009 Apr 16. PMID:19499593 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Beta-Hexosaminidase Beta-Hexosaminidase 3D structures

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