Conformational flexibility of the glycosidase NagZ allows it to bind structurally diverse inhibitors to suppress β-lactam antibiotic resistance.
Identifieur interne : 000F32 ( Main/Exploration ); précédent : 000F31; suivant : 000F33Conformational 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
Affiliations:
- Australie, Canada, France
- Manitoba, Poitou-Charentes
- Poitiers, Winnipeg
- Université de Poitiers, Université du Manitoba
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Le document en format XML
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Stubbs</name><affiliation wicri:level="1"><nlm:affiliation>School of Molecular Sciences, University of Western Australia, Crawley, Western Australia, 6009, Australia.</nlm:affiliation><country xml:lang="fr">Australie</country><wicri:regionArea>School of Molecular Sciences, University of Western Australia, Crawley, Western Australia, 6009</wicri:regionArea><wicri:noRegion>6009</wicri:noRegion></affiliation></author><author><name sortKey="Desire, Jerome" sort="Desire, Jerome" uniqKey="Desire J" first="Jérôme" last="Désiré">Jérôme Désiré</name><affiliation wicri:level="4"><nlm:affiliation>IC2MP, UMR CNRS 7285, Équipe "Synthèse Organique" Groupe Glycochimie, Université de Poitiers, 4 rue Michel Brunet, 86073, Poitiers cedex 9, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>IC2MP, UMR CNRS 7285, Équipe "Synthèse Organique" Groupe Glycochimie, Université de Poitiers, 4 rue Michel Brunet, 86073, Poitiers cedex 9</wicri:regionArea><wicri:noRegion>86073, Poitiers cedex 9</wicri:noRegion><orgName type="university">Université de Poitiers</orgName><placeName><settlement type="city">Poitiers</settlement><region type="region" nuts="2">Poitou-Charentes</region></placeName></affiliation></author><author><name sortKey="Bleriot, Yves" sort="Bleriot, Yves" uniqKey="Bleriot Y" first="Yves" last="Blériot">Yves Blériot</name><affiliation wicri:level="4"><nlm:affiliation>IC2MP, UMR CNRS 7285, Équipe "Synthèse Organique" Groupe Glycochimie, Université de Poitiers, 4 rue Michel Brunet, 86073, Poitiers cedex 9, France.</nlm:affiliation><country xml:lang="fr">France</country><wicri:regionArea>IC2MP, UMR CNRS 7285, Équipe "Synthèse Organique" Groupe Glycochimie, Université de Poitiers, 4 rue Michel Brunet, 86073, Poitiers cedex 9</wicri:regionArea><wicri:noRegion>86073, Poitiers cedex 9</wicri:noRegion><orgName type="university">Université de Poitiers</orgName><placeName><settlement type="city">Poitiers</settlement><region type="region" nuts="2">Poitou-Charentes</region></placeName></affiliation></author><author><name sortKey="Vocadlo, David J" sort="Vocadlo, David J" uniqKey="Vocadlo D" first="David J" last="Vocadlo">David J. Vocadlo</name><affiliation><nlm:affiliation>Department of Chemistry, Simon Fraser University, 8888 University Drive, Burnaby, British Columbia, Canada, V5S 1P6.</nlm:affiliation><wicri:noCountry code="subField">V5S 1P6</wicri:noCountry></affiliation></author><author><name sortKey="Mark, Brian L" sort="Mark, Brian L" uniqKey="Mark B" first="Brian L" last="Mark">Brian L. Mark</name><affiliation wicri:level="4"><nlm:affiliation>Department of Microbiology, University of Manitoba, Winnipeg, Manitoba, Canada, R3T2N2.</nlm:affiliation><orgName type="university">Université du Manitoba</orgName><country>Canada</country><placeName><settlement type="city">Winnipeg</settlement><region type="state">Manitoba</region></placeName></affiliation></author></analytic><series><title level="j">Protein science : a publication of the Protein Society</title><idno type="eISSN">1469-896X</idno><imprint><date when="2017" type="published">2017</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>Acetylglucosamine (analogs & derivatives)</term><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></keywords><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></keywords><keywords scheme="MESH" type="chemical" qualifier="analogs & derivatives" xml:lang="en"><term>Acetylglucosamine</term></keywords><keywords scheme="MESH" type="chemical" qualifier="antagonists & inhibitors" xml:lang="en"><term>Escherichia coli Proteins</term><term>Glycoside Hydrolases</term></keywords><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></keywords><keywords scheme="MESH" qualifier="analogues et dérivés" xml:lang="fr"><term>Acétyl-glucosamine</term></keywords><keywords scheme="MESH" qualifier="antagonistes et inhibiteurs" xml:lang="fr"><term>Glycosidases</term><term>Protéines Escherichia coli</term></keywords><keywords scheme="MESH" qualifier="enzymologie" xml:lang="fr"><term>Escherichia coli</term></keywords><keywords scheme="MESH" qualifier="enzymology" xml:lang="en"><term>Escherichia coli</term></keywords><keywords scheme="MESH" qualifier="genetics" xml:lang="en"><term>Escherichia coli</term><term>Escherichia coli Proteins</term><term>Glycoside Hydrolases</term></keywords><keywords scheme="MESH" qualifier="génétique" xml:lang="fr"><term>Escherichia coli</term><term>Glycosidases</term><term>Protéines Escherichia coli</term></keywords><keywords scheme="MESH" xml:lang="en"><term>Protein Domains</term><term>Protein Structure, Secondary</term><term>beta-Lactam Resistance</term></keywords><keywords scheme="MESH" xml:lang="fr"><term>Acétyl-glucosamine</term><term>Domaines protéiques</term><term>Glycosidases</term><term>Oximes</term><term>Phényl-carbamates</term><term>Protéines Escherichia coli</term><term>Résistance aux bêta-lactamines</term><term>Structure secondaire des protéines</term></keywords></textClass></profileDesc></teiHeader><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></front></TEI><affiliations><list><country><li>Australie</li><li>Canada</li><li>France</li></country><region><li>Manitoba</li><li>Poitou-Charentes</li></region><settlement><li>Poitiers</li><li>Winnipeg</li></settlement><orgName><li>Université de Poitiers</li><li>Université du Manitoba</li></orgName></list><tree><noCountry><name sortKey="Vocadlo, David J" sort="Vocadlo, David J" uniqKey="Vocadlo D" first="David J" last="Vocadlo">David J. Vocadlo</name></noCountry><country name="Canada"><region name="Manitoba"><name sortKey="Vadlamani, Grishma" sort="Vadlamani, Grishma" uniqKey="Vadlamani G" first="Grishma" last="Vadlamani">Grishma Vadlamani</name></region><name sortKey="Mark, Brian L" sort="Mark, Brian L" uniqKey="Mark B" first="Brian L" last="Mark">Brian L. Mark</name></country><country name="Australie"><noRegion><name sortKey="Stubbs, Keith A" sort="Stubbs, Keith A" uniqKey="Stubbs K" first="Keith A" last="Stubbs">Keith A. Stubbs</name></noRegion></country><country name="France"><region name="Poitou-Charentes"><name sortKey="Desire, Jerome" sort="Desire, Jerome" uniqKey="Desire J" first="Jérôme" last="Désiré">Jérôme Désiré</name></region><name sortKey="Bleriot, Yves" sort="Bleriot, Yves" uniqKey="Bleriot Y" first="Yves" last="Blériot">Yves Blériot</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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