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The channel-forming colicins are plasmid-encoded bacteriocins that kill E. coli and related cells and whose mode of action is of interest in related problems of protein import and toxicology. Colicins parasitize metabolite receptors in the outer membrane and translocate across the periplasm with the aid of the Tol or Ton protein systems. X-ray structure(More)
Bacterial enoyl-ACP reductase (FabI) is responsible for catalyzing the final step of bacterial fatty acid biosynthesis and is an attractive target for the development of novel antibacterial agents. Previously we reported the development of FabI inhibitor 4 with narrow spectrum antimicrobial activity and in vivo efficacy against Staphylococcus aureus via(More)
The crystal structure of Escherichia coli tRNA (guanosine-1) methyltransferase (TrmD) complexed with S-adenosyl homocysteine (AdoHcy) has been determined at 2.5A resolution. TrmD, which methylates G37 of tRNAs containing the sequence G36pG37, is a homo-dimer. Each monomer consists of a C-terminal domain connected by a flexible linker to an N-terminal(More)
The X-ray crystal structure of the proform of human matrix metalloproteinase MMP9 has been solved to 2.5 A resolution. The construct includes the prodomain, the catalytic domain and three FnII (fibronectin type II) domains. The prodomain is inserted into the active-site cleft, blocking access to the catalytic zinc. Comparison with the crystal structure of(More)
BACKGROUND Channel-forming colicins, including colicin E1, are a sub-family of bacteriocins. The toxic action of colicin E1 is derived from its ability to form a voltage-gated channel, which causes depolarization of the cytoplasmic membrane of sensitive Escherichia coli cells. In this process, the toxin-like colicin E1 molecule must undergo a substantial(More)
The structure of the ternary complex between ovine placental lactogen (oPL) and the extracellular domain (ECD) of the rat prolactin receptor (rPRLR) reveals that two rPRLR ECDs bind to opposite sides of oPL with pseudo two-fold symmetry. The two oPL receptor binding sites differ significantly in their topography and electrostatic character. These binding(More)
Phosphoinositide 3-kinase α (PI3Kα) is a critical regulator of cell growth and transformation, and its signaling pathway is the most commonly mutated pathway in human cancers. The mammalian target of rapamycin (mTOR), a class IV PI3K protein kinase, is also a central regulator of cell growth, and mTOR inhibitors are believed to augment the antiproliferative(More)
The discovery, proposed binding mode, and optimization of a novel class of Rho-kinase inhibitors are presented. Appropriate substitution on the 6-position of the azabenzimidazole core provided subnanomolar enzyme potency in vitro while dramatically improving selectivity over a panel of other kinases. Pharmacokinetic data was obtained for the most potent and(More)
The biological activities of ovine (o) and bovine (b) placental lactogens (PLs) and their mutated analogues were compared using several binding and in vitro bioassays. In almost all cases, the biological activities of these analogues mediated through rat (r) prolactin receptor (PRLR) showed little or no change, despite a remarkable decrease in their(More)
Growth hormone and prolactin control somato-lactogenic biology. While high-resolution crystal structures have been determined for receptor complexes of human growth hormone, no such information exists for prolactin. A stable 1:2 complex was formed between ovine placental lactogen, a close prolactin homologue, and two copies of the extracellular portion of(More)