Learn More
E1 enzymes activate ubiquitin (Ub) and ubiquitin-like (Ubl) proteins in two steps by carboxy-terminal adenylation and thioester bond formation to a conserved catalytic cysteine in the E1 Cys domain. The structural basis for these intermediates remains unknown. Here we report crystal structures for human SUMO E1 in complex with SUMO adenylate and tetrahedral(More)
Existing drugs address a relatively narrow range of biological targets. As a result, libraries of drug-like molecules have proven ineffective against a variety of challenging targets, such as protein-protein interactions, nucleic acid complexes, and antibacterial modalities. In contrast, natural products are known to be effective at modulating such targets,(More)
Mycobacterium tuberculosis and Yersinia pestis, the causative agents of tuberculosis and plague, respectively, are pathogens with serious ongoing impact on global public health and potential use as agents of bioterrorism. Both pathogens have iron acquisition systems based on siderophores, secreted iron-chelating compounds with extremely high Fe3+ affinity.(More)
Phenolic glycolipids (PGLs) are polyketide-derived virulence factors produced by Mycobacterium tuberculosis, M. leprae, and other mycobacterial pathogens. We have combined bioinformatic, genetic, biochemical, and chemical biology approaches to illuminate the mechanism of chain initiation required for assembly of the p-hydroxyphenyl-polyketide moiety of(More)
Diversity-oriented synthesis (DOS) is an emerging field involving the synthesis of combinatorial libraries of diverse small molecules for biological screening. Rather than being directed toward a single biological target, DOS libraries can be used to identify new ligands for a variety of targets. Several different strategies for library design have been(More)
(-)-Shikimic acid, 3, was converted into both enantiomers of epoxycyclohexenol carboxylic acid, 7, which were attached to a solid support via a photocleavable linker. Tandem acylation-1,3-dipolar cycloaddition with nitrones 11a-g yielded tetracyclic templates 12a-g. After development of several efficient coupling reactions of iodobenzyl tetracycles 12b-d(More)
Menaquinone (vitamin K(2)) is an essential component of the electron transfer chain in many pathogens, including Mycobacterium tuberculosis and Staphylococcus aureus, and menaquinone biosynthesis is a potential target for antibiotic drug discovery. We report herein a series of mechanism-based inhibitors of MenE, an acyl-CoA synthetase that catalyzes(More)
Tri-Institutional Training Program in Chemical Biology, Tri-Institutional Research Program and Molecular Pharmacology & Chemistry Program, Memorial Sloan-Kettering Cancer Center, 1275 York AVenue, Box 422, New York, New York 10021, and Department of Microbiology & Immunology and Molecular Biology Program, Weill Medical College of Cornell UniVersity, 1300(More)
Macrocycles are key structural elements in numerous bioactive small molecules and are attractive targets in the diversity-oriented synthesis of natural product-based libraries. However, efficient and systematic access to diverse collections of macrocycles has proven difficult using classical macrocyclization reactions. To address this problem, we have(More)