4HZM

Crystal structure of Salmonella typhimurium family 3 glycoside hydrolase (NagZ) bound to N-[(3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl]butanamide

Summary for 4HZM

• Entry DOI: 10.2210/pdb4hzm/pdb
• Related: 4GVF 4GVG 4GVH 4GVI
• Descriptor: Beta-hexosaminidase, N-[(3S,4R,5R,6R)-4,5-dihydroxy-6-(hydroxymethyl)piperidin-3-yl]butanamide, 2-(N-MORPHOLINO)-ETHANESULFONIC ACID, ... (4 entities in total)
• Functional Keywords: tim-barrel, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Salmonella enterica subsp. enterica serovar Typhimurium
• Cellular location: Cytoplasm (By similarity): Q8ZQ06
• Total number of polymer chains: 2
• Total formula weight: 78107.66

Authors

Bacik, J.P.,Mark, B.L. (deposition date: 2012-11-15, release date: 2013-06-19, Last modification date: 2023-09-20)

Primary citation

Stubbs, K.A.,Bacik, J.P.,Perley-Robertson, G.E.,Whitworth, G.E.,Gloster, T.M.,Vocadlo, D.J.,Mark, B.L.
The Development of Selective Inhibitors of NagZ: Increased Susceptibility of Gram-Negative Bacteria to beta-Lactams.
Chembiochem, 14:1973-1981, 2013

PubMed Abstract: The increasing incidence of inducible chromosomal AmpC β-lactamases within the clinic is a growing concern because these enzymes deactivate a broad range of even the most recently developed β-lactam antibiotics. As a result, new strategies are needed to block the action of this antibiotic resistance enzyme. Presented here is a strategy to combat the action of inducible AmpC by inhibiting the β-glucosaminidase NagZ, which is an enzyme involved in regulating the induction of AmpC expression. A divergent route facilitating the rapid synthesis of a series of N-acyl analogues of 2-acetamido-2-deoxynojirimycin is reported here. Among these compounds are potent NagZ inhibitors that are selective against functionally related human enzymes. These compounds reduce minimum inhibitory concentration values for β-lactams against a clinically relevant Gram-negative bacterium bearing inducible chromosomal AmpC β-lactamase, Pseudomonas aeruginosa. The structure of a NagZ-inhibitor complex provides insight into the molecular basis for inhibition by these compounds.

PubMed: 24009110
DOI: 10.1002/cbic.201300395

Experimental method

X-RAY DIFFRACTION (1.45 Å)