Journal ArticleDOI
A mechanism of drug action revealed by structural studies of enoyl reductase.
Clair Baldock,John B. Rafferty,Svetlana E. Sedelnikova,Patrick J. Baker,Antoine R. Stuitje,Antoni R. Slabas,Timothy Robert Hawkes,David W. Rice +7 more
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TLDR
Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazabadine revealed the formation of a covalent bond between the 2′ hydroxyl of the nicotinamia ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analog.Abstract:
Enoyl reductase (ENR), an enzyme involved in fatty acid biosynthesis, is the target for antibacterial diazaborines and the front-line antituberculosis drug isoniazid. Analysis of the structures of complexes of Escherichia coli ENR with nicotinamide adenine dinucleotide and either thienodiazaborine or benzodiazaborine revealed the formation of a covalent bond between the 2' hydroxyl of the nicotinamide ribose and a boron atom in the drugs to generate a tight, noncovalently bound bisubstrate analog. This analysis has implications for the structure-based design of inhibitors of ENR, and similarities to other oxidoreductases suggest that mimicking this molecular linkage may have generic applications in other areas of medicinal chemistry.read more
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The structural biology of type ii fatty acid biosynthesis
TL;DR: High-resolution X-ray and/or NMR structures of representative members of every enzyme in the type II pathway are now available, revealing the specific three-dimensional features of the enzymes that explain substrate recognition, chain length specificity, and the catalytic mechanisms that define their roles in producing the multitude of products generated by thetype II system.
Journal ArticleDOI
Modification of the NADH of the Isoniazid Target (InhA) from Mycobacterium tuberculosis
TL;DR: Data from x-ray crystallography and mass spectrometry reveal that the mechanism of isoniazid action against InhA is covalent attachment of the activated form of the drug to the Nicotinamide ring of nicotinamide adenine dinucleotide bound within the active site of Inh A.
Journal ArticleDOI
Structural and functional organization of the animal fatty acid synthase.
TL;DR: A revised model for the fatty acid synthase is suggested in which the two polypeptides are oriented such that head-to-tail contacts are formed both between and within subunits.
Journal ArticleDOI
Associative learning disrupted by impaired Gs signaling in Drosophila mushroom bodies
John B. Connolly,Ian J. H. Roberts,J. Douglas Armstrong,Kim Kaiser,Michael Forte,Tim Tully,Cahir J. O'Kane +6 more
TL;DR: Olfactory learning depends on regulated Gs signaling in Drosophila MBs, and the ability to associate odors with electroshock was abolished when Gαs* was targeted to MB, but not CC, structures, whereas sensorimotor responses to these stimuli remained normal.
Journal ArticleDOI
Mechanism of Triclosan Inhibition of Bacterial Fatty Acid Synthesis
TL;DR: Formation of a noncovalent “bi-substrate” complex accounts for the effectiveness of triclosan as a FabI inhibitor and illustrates that mutations in the FabI active site that interfere with the formation of a stable FabI-NAD+-triclosan ternary complex acquire resistance to the drug.
References
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MOLSCRIPT: a program to produce both detailed and schematic plots of protein structures
TL;DR: The MOLSCRIPT program as discussed by the authors produces plots of protein structures using several different kinds of representations, including simple wire models, ball-and-stick models, CPK models and text labels.
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LIGPLOT: a program to generate schematic diagrams of protein-ligand interactions
TL;DR: The LIGPLOT program automatically generates schematic 2-D representations of protein-ligand complexes from standard Protein Data Bank file input giving a simple and informative representation of the intermolecular interactions and their strengths, including hydrogen bonds, hydrophobic interactions and atom accessibilities.
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A graphics model building and refinement system for macromolecules
TL;DR: A model building and refinement system is described for use with a Vector General 3400 display that has been used to assist in difference Fourier map interpretation at medium and high resolution, and to build a protein molecule into a multiple isomorphous replacement phased electron density map.
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From the U. S. A.
TL;DR: In this article, the existence of a monotone interpolating function with the same index set was shown to be necessary and sufficient for continuous interpolating functional if the index set I is finite, but not sufficient if I is infinite.
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inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis
Asesh Banerjee,E. Dubnau,Annaik Quemard,V. Balasubramanian,Kyung Sun Um,T. Wilson,Desmond M. Collins,G.W. de Lisle,William R. Jacobs +8 more
TL;DR: Results suggest that InhA is likely a primary target of action for INH and ETH and that it may be involved in mycolic acid biosynthesis.