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Article: Structure of the LpxC deacetylase with a bound substrate-analog inhibitor

TitleStructure of the LpxC deacetylase with a bound substrate-analog inhibitor
Authors
Issue Date2003
Citation
Nature Structural Biology, 2003, v. 10 n. 8, p. 645-651 How to Cite?
AbstractThe zinc-dependent UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) catalyzes the first committed step in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) that constitutes the outermost monolayer of Gram-negative bacteria. As LpxC is crucial for the survival of Gram-negative organisms and has no sequence homology to known mammalian deacetylases or amidases, it is an excellent target for the design of new antibiotics. The solution structure of LpxC from Aquifex aeolicus in complex with a substrate-analog inhibitor, TU-514, reveals a novel α/β fold, a unique zinc-binding motif and a hydrophobic passage that captures the acyl chain of the inhibitor. On the basis of biochemical and structural studies, we propose a catalytic mechanism for LpxC, suggest a model for substrate binding and provide evidence that mobility and dynamics in structural motifs close to the active site have key roles in the capture of the substrate.
Persistent Identifierhttp://hdl.handle.net/10722/167822
ISSN
2003 Impact Factor: 11.579
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCoggins, BEen_US
dc.contributor.authorLi, Xen_US
dc.contributor.authorMcclerren, ALen_US
dc.contributor.authorHindsgaul, Oen_US
dc.contributor.authorRaetz, CRHen_US
dc.contributor.authorZhou, Pen_US
dc.date.accessioned2012-10-08T03:11:59Z-
dc.date.available2012-10-08T03:11:59Z-
dc.date.issued2003en_US
dc.identifier.citationNature Structural Biology, 2003, v. 10 n. 8, p. 645-651en_US
dc.identifier.issn1072-8368en_US
dc.identifier.urihttp://hdl.handle.net/10722/167822-
dc.description.abstractThe zinc-dependent UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) catalyzes the first committed step in the biosynthesis of lipid A, the hydrophobic anchor of lipopolysaccharide (LPS) that constitutes the outermost monolayer of Gram-negative bacteria. As LpxC is crucial for the survival of Gram-negative organisms and has no sequence homology to known mammalian deacetylases or amidases, it is an excellent target for the design of new antibiotics. The solution structure of LpxC from Aquifex aeolicus in complex with a substrate-analog inhibitor, TU-514, reveals a novel α/β fold, a unique zinc-binding motif and a hydrophobic passage that captures the acyl chain of the inhibitor. On the basis of biochemical and structural studies, we propose a catalytic mechanism for LpxC, suggest a model for substrate binding and provide evidence that mobility and dynamics in structural motifs close to the active site have key roles in the capture of the substrate.en_US
dc.languageengen_US
dc.relation.ispartofNature Structural Biologyen_US
dc.subject.meshAmidohydrolases - Antagonists & Inhibitors - Chemistry - Geneticsen_US
dc.subject.meshAmino Acid Sequenceen_US
dc.subject.meshAnti-Bacterial Agents - Chemistry - Pharmacologyen_US
dc.subject.meshCatalytic Domainen_US
dc.subject.meshDrug Designen_US
dc.subject.meshEnzyme Inhibitors - Chemistry - Pharmacologyen_US
dc.subject.meshEscherichia Coli - Enzymology - Geneticsen_US
dc.subject.meshGram-Negative Bacteria - Enzymology - Geneticsen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshMolecular Sequence Dataen_US
dc.subject.meshNuclear Magnetic Resonance, Biomolecularen_US
dc.subject.meshProtein Conformationen_US
dc.subject.meshRecombinant Proteins - Antagonists & Inhibitors - Chemistry - Geneticsen_US
dc.subject.meshSequence Homology, Amino Aciden_US
dc.subject.meshSubstrate Specificityen_US
dc.subject.meshZinc - Chemistryen_US
dc.titleStructure of the LpxC deacetylase with a bound substrate-analog inhibitoren_US
dc.typeArticleen_US
dc.identifier.emailLi, X:xuechenl@hku.hken_US
dc.identifier.authorityLi, X=rp00742en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1038/nsb948en_US
dc.identifier.pmid12833153-
dc.identifier.scopuseid_2-s2.0-0042123525en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-0042123525&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume10en_US
dc.identifier.issue8en_US
dc.identifier.spage645en_US
dc.identifier.epage651en_US
dc.identifier.isiWOS:000184412400014-
dc.identifier.f10001015024-
dc.identifier.scopusauthoridCoggins, BE=6507075734en_US
dc.identifier.scopusauthoridLi, X=24168958800en_US
dc.identifier.scopusauthoridMcClerren, AL=7801327115en_US
dc.identifier.scopusauthoridHindsgaul, O=7102966220en_US
dc.identifier.scopusauthoridRaetz, CRH=7102514726en_US
dc.identifier.scopusauthoridZhou, P=7401848622en_US

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