Ligand-gated ion channels

Ivermectin and nodulosporic acid receptors in Drosophila melanogaster contain both γ-aminobutyric acid-gated Rdl and glutamate-gated GluClα chloride channel subunitsLudmerer, S. W. et al. Biochemistry 41, 6548–6560 (2002)

Ligand-gated chloride channels are the targets for several insecticides, such as ivermectin and nodulisporic acid (see the Review by Raymond and Satelle on page 427 of the June issue), but the subunit composition of these channels is poorly characterized. Ludmerer et al. provide the first biochemical and immunological evidence of co-assembly of subunits from two different subclasses of ligand-gated-ion-channel subunit.

High-throughput screening

High-throughput NMR-based screening with competition binding experimentsDalvit, C. et al. J. Am. Chem. Soc. 2002 June 6 (doi: 10.1021/ja020174b)

In recent years, NMR has emerged as a powerful method for the detection of small molecules that interact with macromolecular targets of therapeutic interest (see the Review by Wüthrich and colleagues on page 211 of the March issue). However, ligand-based NMR screening methods are limited in their ability to detect high-affinity molecules. Dalvit et al. describe an approach that can overcome this limitation, and which also permits detection of high-affinity molecules that are only marginally soluble, thus enlarging the diversity of compounds that are amenable to NMR screening.

Antipyretics

Determinants of the cellular specificity of acetaminophen as an inhibitor of prostaglandin H2 synthasesBoutard, O. et al. Proc. Natl Acad. Sci. USA 99, 7130–7135 (2002)

Acetaminophen has anti-fever properties, but unlike other inhibitors of the biosynthesis of prostaglandins, it has little effect on inflammation or platelets. Boutard et al. provide evidence that high concentrations of hydroperoxide byproducts counteract the inhibitory effect of acetaminophen on prostaglandin H synthase in platelets and inflammatory cells, indicating that the properties of acetaminophen might be accounted for by differing concentrations of hydroperoxides in cells associated with the inflammatory response and cells associated with fever.

Rational drug design

Disabling receptor ensembles with rationally designed interface peptidomimeticsBerezov, A. et al. J. Biol. Chem. 2002 May 14 (doi: 10.1074/jbc.M202880200)

Homo- and heterodimerization of erbB-family receptor tyrosine kinases — which are overexpressed in various cancers — is known to be important in receptor signalling. Berezov et al. describe the design of peptides derived from potential dimerization surfaces in an extracellular subdomain of the erbB receptors, which can suppress growth in cells overexpressing erbB receptors.