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Article: Mechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase

TitleMechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylase
Authors
Issue Date2006
PublisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry
Citation
Biochemistry, 2006, v. 45 n. 26, p. 7940-7948 How to Cite?
AbstractThe metal-dependent deacetylase LpxC catalyzes the first committed step of lipid A biosynthesis in Gram-negative bacteria. Accordingly, LpxC is an attractive target for the development of inhibitors that may serve as potential new antibiotics for the treatment of Gram-negative bacterial infections. Here, we report the 2.7 A resolution X-ray crystal structure of LpxC complexed with the substrate analogue inhibitor TU-514 and the 2.0 A resolution structure of LpxC complexed with imidazole. The X-ray crystal structure of LpxC complexed with TU-514 allows for a detailed examination of the coordination geometry of the catalytic zinc ion and other enzyme-inhibitor interactions in the active site. The hydroxamate group of TU-514 forms a bidentate chelate complex with the zinc ion and makes hydrogen bond interactions with conserved active site residues E78, H265, and T191. The inhibitor C-4 hydroxyl group makes direct hydrogen bond interactions with E197 and H58. Finally, the C-3 myristate moiety of the inhibitor binds in the hydrophobic tunnel of the active site. These intermolecular interactions provide a foundation for understanding structural aspects of enzyme-substrate and enzyme-inhibitor affinity. Comparison of the TU-514 complex with cacodylate and imidazole complexes suggests a possible substrate diphosphate binding site and highlights residues that may stabilize the tetrahedral intermediate and its flanking transition states in catalysis. Evidence of a catalytic zinc ion in the native zinc enzyme coordinated by H79, H238, D242, and two water molecules with square pyramidal geometry is also presented. These results suggest that the native state of this metallohydrolase may contain a pentacoordinate zinc ion, which contrasts with the native states of archetypical zinc hydrolases such as thermolysin and carboxypeptidase A. © 2006 American Chemical Society.
Persistent Identifierhttp://hdl.handle.net/10722/168025
ISSN
2015 Impact Factor: 2.876
2015 SCImago Journal Rankings: 1.769
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorGennadios, HAen_US
dc.contributor.authorWhittington, DAen_US
dc.contributor.authorLi, Xen_US
dc.contributor.authorFierke, CAen_US
dc.contributor.authorChristianson, DWen_US
dc.date.accessioned2012-10-08T03:14:17Z-
dc.date.available2012-10-08T03:14:17Z-
dc.date.issued2006en_US
dc.identifier.citationBiochemistry, 2006, v. 45 n. 26, p. 7940-7948en_US
dc.identifier.issn0006-2960en_US
dc.identifier.urihttp://hdl.handle.net/10722/168025-
dc.description.abstractThe metal-dependent deacetylase LpxC catalyzes the first committed step of lipid A biosynthesis in Gram-negative bacteria. Accordingly, LpxC is an attractive target for the development of inhibitors that may serve as potential new antibiotics for the treatment of Gram-negative bacterial infections. Here, we report the 2.7 A resolution X-ray crystal structure of LpxC complexed with the substrate analogue inhibitor TU-514 and the 2.0 A resolution structure of LpxC complexed with imidazole. The X-ray crystal structure of LpxC complexed with TU-514 allows for a detailed examination of the coordination geometry of the catalytic zinc ion and other enzyme-inhibitor interactions in the active site. The hydroxamate group of TU-514 forms a bidentate chelate complex with the zinc ion and makes hydrogen bond interactions with conserved active site residues E78, H265, and T191. The inhibitor C-4 hydroxyl group makes direct hydrogen bond interactions with E197 and H58. Finally, the C-3 myristate moiety of the inhibitor binds in the hydrophobic tunnel of the active site. These intermolecular interactions provide a foundation for understanding structural aspects of enzyme-substrate and enzyme-inhibitor affinity. Comparison of the TU-514 complex with cacodylate and imidazole complexes suggests a possible substrate diphosphate binding site and highlights residues that may stabilize the tetrahedral intermediate and its flanking transition states in catalysis. Evidence of a catalytic zinc ion in the native zinc enzyme coordinated by H79, H238, D242, and two water molecules with square pyramidal geometry is also presented. These results suggest that the native state of this metallohydrolase may contain a pentacoordinate zinc ion, which contrasts with the native states of archetypical zinc hydrolases such as thermolysin and carboxypeptidase A. © 2006 American Chemical Society.en_US
dc.languageengen_US
dc.publisherAmerican Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistryen_US
dc.relation.ispartofBiochemistryen_US
dc.subject.meshAmidohydrolases - Chemistry - Metabolismen_US
dc.subject.meshBacterial Proteins - Chemistry - Metabolismen_US
dc.subject.meshComputer Simulationen_US
dc.subject.meshCrystallography, X-Rayen_US
dc.subject.meshEnzyme Inhibitors - Pharmacologyen_US
dc.subject.meshKineticsen_US
dc.subject.meshLigandsen_US
dc.subject.meshLipid A - Biosynthesisen_US
dc.subject.meshModels, Molecularen_US
dc.subject.meshProtein Bindingen_US
dc.subject.meshProtein Conformationen_US
dc.titleMechanistic inferences from the binding of ligands to LpxC, a metal-dependent deacetylaseen_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.doi10.1021/bi060823men_US
dc.identifier.pmid16800620-
dc.identifier.scopuseid_2-s2.0-33745602267en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-33745602267&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume45en_US
dc.identifier.issue26en_US
dc.identifier.spage7940en_US
dc.identifier.epage7948en_US
dc.identifier.isiWOS:000238558700002-
dc.publisher.placeUnited Statesen_US
dc.identifier.scopusauthoridGennadios, HA=8957309700en_US
dc.identifier.scopusauthoridWhittington, DA=7006068253en_US
dc.identifier.scopusauthoridLi, X=24168958800en_US
dc.identifier.scopusauthoridFierke, CA=7004555995en_US
dc.identifier.scopusauthoridChristianson, DW=7004992085en_US

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