جهت دسترسی به کاربرگه ی زیر، از این لینک استفاده کنید. http://dl.pgu.ac.ir/handle/10722/167891
Title: Refined solution structure of the LpxC-TU-514 complex and pK a analysis of an active site histidine: Insights into the mechanism and inhibitor design
Keywords: Amidohydrolases - Antagonists & Inhibitors - Chemistry - Genetics;Aquifoliaceae - Enzymology - Genetics;Binding Sites - Genetics;Catalysis;Conserved Sequence - Genetics;Crystallography, X-Ray;Enzyme Inhibitors - Chemical Synthesis;Glycolipids - Chemical Synthesis;Hexoses - Chemistry;Histidine - Chemistry - Genetics;Hydrogen-Ion Concentration;Mutagenesis, Site-Directed;Nuclear Magnetic Resonance, Biomolecular - Methods;Protons;Solutions;Substrate Specificity - Genetics;Thermodynamics
Publisher: American Chemical Society. The Journal's web site is located at http://pubs.acs.org/biochemistry;United States
Description: Lipopolysaccharide, the major constituent of the outer monolayer of the outer membrane of Gram-negative bacteria, is anchored into the membrane through the hydrophobic moiety lipid A, a hexaacylated disaccharide. The zinc-dependent metalloamidase UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC) catalyzes the second and committed step in the biosynthesis of lipid A. LpxC shows no homology to mammalian metalloamidases and is essential for cell viability, making it an important target for the development of novel antibacterial compounds. Recent NMR and X-ray studies of the LpxC from Aquifex aeolicus have provided the first structural information about this family of proteins. Insight into the catalytic mechanism and the design of effective inhibitors could be facilitated by more detailed structural and biochemical studies that define substrate-protein interactions and the roles of specific residues in the active site. Here, we report the synthesis of the 13C-labeled substrate-analogue inhibitor TU-514, and the subsequent refinement of the solution structure of the A. aeolicus LpxC-TU-514 complex using residual dipolar couplings. We also reevaluate the catalytic role of an active site histidine, H253, on the basis of both its pK a as determined by NMR titration and pH-dependent kinetic analyses. These results provide a structural basis for the design of more potent LpxC inhibitors than those that are currently available.;link_to_subscribed_fulltext
Other Identifiers: Biochemistry, 2005, v. 44 n. 4, p. 1114-1126
10.1021/bi047820z
1126
WOS:000226594800004
0006-2960
4
15667205
eid_2-s2.0-13444287735
1114
http://hdl.handle.net/10722/167891
44
Type Of Material: Article
Appears in Collections:Department of Chemistry

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