Conformational flexibility of the glycosidase NagZ allows it to bind structurally diverse inhibitors to suppress β-lactam antibiotic resistance.
Identifieur interne : 004572 ( Ncbi/Curation ); précédent : 004571; suivant : 004573Conformational flexibility of the glycosidase NagZ allows it to bind structurally diverse inhibitors to suppress β-lactam antibiotic resistance.
Auteurs : Grishma Vadlamani [Canada] ; Keith A. Stubbs [Australie] ; Jérôme Désiré [France] ; Yves Blériot [France] ; David J. Vocadlo ; Brian L. Mark [Canada]Source :
- Protein science : a publication of the Protein Society [ 1469-896X ] ; 2017.
Descripteurs français
- KwdFr :
- Acétyl-glucosamine (), Acétyl-glucosamine (analogues et dérivés), Domaines protéiques, Escherichia coli (enzymologie), Escherichia coli (génétique), Glycosidases (), Glycosidases (antagonistes et inhibiteurs), Glycosidases (génétique), Oximes (), Phényl-carbamates (), Protéines Escherichia coli (), Protéines Escherichia coli (antagonistes et inhibiteurs), Protéines Escherichia coli (génétique), Résistance aux bêta-lactamines, Structure secondaire des protéines.
- MESH :
- analogues et dérivés : Acétyl-glucosamine.
- antagonistes et inhibiteurs : Glycosidases, Protéines Escherichia coli.
- enzymologie : Escherichia coli.
- génétique : Escherichia coli, Glycosidases, Protéines Escherichia coli.
- Acétyl-glucosamine, Domaines protéiques, Glycosidases, Oximes, Phényl-carbamates, Protéines Escherichia coli, Résistance aux bêta-lactamines, Structure secondaire des protéines.
English descriptors
- KwdEn :
- Acetylglucosamine (analogs & derivatives), Acetylglucosamine (chemistry), Escherichia coli (enzymology), Escherichia coli (genetics), Escherichia coli Proteins (antagonists & inhibitors), Escherichia coli Proteins (chemistry), Escherichia coli Proteins (genetics), Glycoside Hydrolases (antagonists & inhibitors), Glycoside Hydrolases (chemistry), Glycoside Hydrolases (genetics), Oximes (chemistry), Phenylcarbamates (chemistry), Protein Domains, Protein Structure, Secondary, beta-Lactam Resistance.
- MESH :
- chemical , analogs & derivatives : Acetylglucosamine.
- chemical , antagonists & inhibitors : Escherichia coli Proteins, Glycoside Hydrolases.
- chemical , chemistry : Acetylglucosamine, Escherichia coli Proteins, Glycoside Hydrolases, Oximes, Phenylcarbamates.
- enzymology : Escherichia coli.
- genetics : Escherichia coli, Escherichia coli Proteins, Glycoside Hydrolases.
- Protein Domains, Protein Structure, Secondary, beta-Lactam Resistance.
Abstract
NagZ is an N-acetyl-β-d-glucosaminidase that participates in the peptidoglycan (PG) recycling pathway of Gram-negative bacteria by removing N-acetyl-glucosamine (GlcNAc) from PG fragments that have been excised from the cell wall during growth. The 1,6-anhydromuramoyl-peptide products generated by NagZ activate β-lactam resistance in many Gram-negative bacteria by inducing the expression of AmpC β-lactamase. Blocking NagZ activity can thereby suppress β-lactam antibiotic resistance in these bacteria. The NagZ active site is dynamic and it accommodates distortion of the glycan substrate during catalysis using a mobile catalytic loop that carries a histidine residue which serves as the active site general acid/base catalyst. Here, we show that flexibility of this catalytic loop also accommodates structural differences in small molecule inhibitors of NagZ, which could be exploited to improve inhibitor specificity. X-ray structures of NagZ bound to the potent yet non-selective N-acetyl-β-glucosaminidase inhibitor PUGNAc (O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate), and two NagZ-selective inhibitors - EtBuPUG, a PUGNAc derivative bearing a 2-N-ethylbutyryl group, and MM-156, a 3-N-butyryl trihydroxyazepane, revealed that the phenylcarbamate moiety of PUGNAc and EtBuPUG completely displaces the catalytic loop from the NagZ active site to yield a catalytically incompetent form of the enzyme. In contrast, the catalytic loop was found positioned in the catalytically active conformation within the NagZ active site when bound to MM-156, which lacks the phenylcarbamate extension. Displacement of the catalytic loop by PUGNAc and its N-acyl derivative EtBuPUG alters the active site conformation of NagZ, which presents an additional strategy to improve the potency and specificity of NagZ inhibitors.
DOI: 10.1002/pro.3166
PubMed: 28370529
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David J. Vocadlo<affiliation><nlm:affiliation>Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada, V5S 1P6.</nlm:affiliation>
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<term>Acetylglucosamine (chemistry)</term>
<term>Escherichia coli (enzymology)</term>
<term>Escherichia coli (genetics)</term>
<term>Escherichia coli Proteins (antagonists & inhibitors)</term>
<term>Escherichia coli Proteins (chemistry)</term>
<term>Escherichia coli Proteins (genetics)</term>
<term>Glycoside Hydrolases (antagonists & inhibitors)</term>
<term>Glycoside Hydrolases (chemistry)</term>
<term>Glycoside Hydrolases (genetics)</term>
<term>Oximes (chemistry)</term>
<term>Phenylcarbamates (chemistry)</term>
<term>Protein Domains</term>
<term>Protein Structure, Secondary</term>
<term>beta-Lactam Resistance</term>
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<keywords scheme="KwdFr" xml:lang="fr"><term>Acétyl-glucosamine ()</term>
<term>Acétyl-glucosamine (analogues et dérivés)</term>
<term>Domaines protéiques</term>
<term>Escherichia coli (enzymologie)</term>
<term>Escherichia coli (génétique)</term>
<term>Glycosidases ()</term>
<term>Glycosidases (antagonistes et inhibiteurs)</term>
<term>Glycosidases (génétique)</term>
<term>Oximes ()</term>
<term>Phényl-carbamates ()</term>
<term>Protéines Escherichia coli ()</term>
<term>Protéines Escherichia coli (antagonistes et inhibiteurs)</term>
<term>Protéines Escherichia coli (génétique)</term>
<term>Résistance aux bêta-lactamines</term>
<term>Structure secondaire des protéines</term>
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<keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Escherichia coli Proteins</term>
<term>Glycoside Hydrolases</term>
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<keywords scheme="MESH" type="chemical" qualifier="chemistry" xml:lang="en"><term>Acetylglucosamine</term>
<term>Escherichia coli Proteins</term>
<term>Glycoside Hydrolases</term>
<term>Oximes</term>
<term>Phenylcarbamates</term>
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<front><div type="abstract" xml:lang="en">NagZ is an N-acetyl-β-d-glucosaminidase that participates in the peptidoglycan (PG) recycling pathway of Gram-negative bacteria by removing N-acetyl-glucosamine (GlcNAc) from PG fragments that have been excised from the cell wall during growth. The 1,6-anhydromuramoyl-peptide products generated by NagZ activate β-lactam resistance in many Gram-negative bacteria by inducing the expression of AmpC β-lactamase. Blocking NagZ activity can thereby suppress β-lactam antibiotic resistance in these bacteria. The NagZ active site is dynamic and it accommodates distortion of the glycan substrate during catalysis using a mobile catalytic loop that carries a histidine residue which serves as the active site general acid/base catalyst. Here, we show that flexibility of this catalytic loop also accommodates structural differences in small molecule inhibitors of NagZ, which could be exploited to improve inhibitor specificity. X-ray structures of NagZ bound to the potent yet non-selective N-acetyl-β-glucosaminidase inhibitor PUGNAc (O-(2-acetamido-2-deoxy-d-glucopyranosylidene) amino-N-phenylcarbamate), and two NagZ-selective inhibitors - EtBuPUG, a PUGNAc derivative bearing a 2-N-ethylbutyryl group, and MM-156, a 3-N-butyryl trihydroxyazepane, revealed that the phenylcarbamate moiety of PUGNAc and EtBuPUG completely displaces the catalytic loop from the NagZ active site to yield a catalytically incompetent form of the enzyme. In contrast, the catalytic loop was found positioned in the catalytically active conformation within the NagZ active site when bound to MM-156, which lacks the phenylcarbamate extension. Displacement of the catalytic loop by PUGNAc and its N-acyl derivative EtBuPUG alters the active site conformation of NagZ, which presents an additional strategy to improve the potency and specificity of NagZ inhibitors.</div>
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