Cell Chemical Biology
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Sep 01, 2006

Volume 13Issue 9p919-1010
Open Archive


  • Spray-On Special Effects Mendel Biotechnology Uses Chemical Genetics to Help Plants Cope with Stress

    • Wendy Wolfson
    Agriculture has always been at the mercy of the elements and blessed by the gods. But instead of praying for rain, farmers in the near future may use chemical genetics to help crops better cope with heat, cold, and drought. Chemical genetics uses small molecules to modulate biochemical pathways to discover how gene products function. If, in plants, this method is implemented on transcription factors that regulate gene expression, it can complement selective breeding or genetic modification of crops, or, in some cases, replace them altogether.


  • Fine-Tuning ER-β Structure with PTMs

    • Gerald W. Hart,
    • Kaoru Sakabe
    Estrogen receptor β is differentially regulated by alternative O-GlcNAcylation/O-phosphorylation at Ser16. NMR, CD, and molecular dynamics analyses of model peptides [1] show that these alternative modifications induce different peptide conformations, providing a molecular basis for their differential regulation of protein function.
  • A Noncanonical Path to Mechanism of Action

    • Randall T. Peterson
    Improved methods for discovering small-molecule mechanisms of action are needed. In this issue of Chemistry & Biology, Zhang et al. [1] make clever use of the zebrafish to study the mechanism of the angiogenesis inhibitor fumagillin and reveal that it targets the noncanonical Wnt pathway.
  • A Stability Switch for Proteins

    • Tim Clackson
    A paper published in the September 8 issue of Cell [1] describes a generally applicable approach for chemical control of protein stability, with potential for broad use in chemical genetics.

Research Articles

  • Replacement Surgery with Unnatural Amino Acids in the Lock-and-Key Joint of Glutathione Transferase Subunits

    • Usama M. Hegazy,
    • Ulf Hellman,
    • Bengt Mannervik
    Proteins contain amino acid residues essential to structure and function. Ribosomal protein synthesis is typically limited to the 20 amino acids of the genetic code, but posttranslational chemical modifications can greatly expand the diversity of side chain functionalities. In this investigation, a natural aromatic residue in the lock-and-key joint at the subunit interface of the dimeric glutathione transferase P1-1 was replaced by an S-alkylcysteine residue to give a functional enzyme. Introduction of Cys in the key position inactivates the enzyme, but subsequent alkylation of this residue enhances the catalytic efficiency up to 27,000-fold.
  • Alternative O-GlcNAcylation/O-Phosphorylation of Ser16 Induce Different Conformational Disturbances to the N Terminus of Murine Estrogen Receptor β

    • Yong-Xiang Chen,
    • Jin-Tang Du,
    • Lian-Xiu Zhou,
    • Xiao-Hong Liu,
    • Yu-Fen Zhao,
    • Hiroshi Nakanishi,
    • Yan-Mei Li
    Serine and threonine residues in many proteins can be modified by either phosphorylation or GlcNAcylation. To investigate the mechanism of O-GlcNAc and O-phosphate's reciprocal roles in modulating the degradation and activity of murine estrogen receptor β (mER-β), the conformational changes induced by O-GlcNAcylation and O-phosphorylation of Ser16 in 17-mer model peptides corresponding to the N-terminal intrinsically disordered (ID) region of mER-β were studied by NMR techniques, circular dichroism (CD), and molecular dynamics simulations.
  • Identification of NanE as the Thioesterase for Polyether Chain Release in Nanchangmycin Biosynthesis

    • Tiangang Liu,
    • Delin You,
    • Chiara Valenzano,
    • Yuhui Sun,
    • Jialiang Li,
    • Qing Yu,
    • Xiufen Zhou,
    • David E. Cane,
    • Zixin Deng
    The polyketide synthase (PKS) for the biosynthesis of the polyether nanchangmycin lacks an apparent thioesterase comparable to the type I thioesterase domains of the modular PKSs responsible for macrolide biosynthesis. Three candidate polyether chain-releasing factors were examined. Both the putative CR domain and the NanE protein appeared to be genetically relevant. Among the three heterologously expressed soluble proteins (recombinant CR domain, the ACP-CR didomain, and NanE) tested, only NanE hydrolyzed the polyether-SNAC.
  • The GSK-3 Inhibitor BIO Promotes Proliferation in Mammalian Cardiomyocytes

    • Ai-Sun Tseng,
    • Felix B. Engel,
    • Mark T. Keating
    The maintenance of self-renewal in stem cells appears to be distinct from the induction of proliferation of the terminally differentiated mammalian cardiomyocytes because it is believed that the latter are unable to divide. However, proliferation is a necessary step in both processes. Interestingly, the small molecule 6-bromoindirubin-3′-oxime (BIO) is the first pharmacological agent shown to maintain self-renewal in human and mouse embryonic stem cells. To determine whether a molecule that can maintain stem cell properties can also participate in controlling the proliferative capability of the highly differentiated cardiomyocytes, we examine the effect of BIO in postmitotic cardiac cells.
  • Small-Molecule Screening Identifies the Selanazal Drug Ebselen as a Potent Inhibitor of DMT1-Mediated Iron Uptake

    • Herbert A. Wetli,
    • Peter D. Buckett,
    • Marianne Wessling-Resnick
    HEK293T cells overexpressing divalent metal transporter-1 (DMT1) were established to screen for small-molecule inhibitors of iron uptake. Using a fluorescence-based assay, we tested 2000 known bioactive compounds to find 3 small molecules that potently block ferrous iron uptake. One of the inhibitors, ebselen, is a seleno compound used in clinical trials as a protective agent against ischemic stroke. Ebselen inhibited Fe(II) uptake (IC50 of ∼0.22 μM), but did not influence Fe(III) transport or DMT1-mediated manganese uptake.
  • Quinocarmycin Analog DX-52-1 Inhibits Cell Migration and Targets Radixin, Disrupting Interactions of Radixin with Actin and CD44

    • Alem W. Kahsai,
    • Shoutian Zhu,
    • Duncan J. Wardrop,
    • William S. Lane,
    • Gabriel Fenteany
    In the course of screening for new small-molecule modulators of cell motility, we discovered that quinocarmycin (also known as quinocarcin) analog DX-52-1 is an inhibitor of epithelial cell migration. While it has been assumed that the main target of DX-52-1 is DNA, we identified and confirmed radixin as the relevant molecular target of DX-52-1 in the cell. Radixin is a member of the ezrin/radixin/moesin family of membrane-actin cytoskeleton linker proteins that also participate in signal transduction pathways.
  • Structural Studies of Vγ2Vδ2 T Cell Phosphoantigens

    • Yonghui Zhang,
    • Yongcheng Song,
    • Fenglin Yin,
    • Erin Broderick,
    • Kathryn Siegel,
    • Amanda Goddard,
    • Edward Nieves,
    • Ljiljana Pasa-Tolic,
    • Yoshimasa Tanaka,
    • Hong Wang,
    • Craig T. Morita,
    • Eric Oldfield
    Human γδ T cells containing the Vγ2Vδ2 (Vγ9Vδ2) T cell receptor are stimulated by a broad variety of small, phosphorus-containing antigenic molecules called phosphoantigens. The structures of several species present in both Mycobacteria (TUBags1–4) and in Escherichia coli have been reported to contain a formyl-alkyl diphosphate core. Here we report the synthesis of the lead member of the series, 3-formyl-1-butyl diphosphate. This compound has low activity for γδ T cell stimulation, unlike its highly active isomer (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate, necessitating a revision of the structure of TUBag1.
  • Synthesis and Testing of a Focused Phenothiazine Library for Binding to HIV-1 TAR RNA

    • Moriz Mayer,
    • P. Therese Lang,
    • Sabina Gerber,
    • Peter B. Madrid,
    • Irene Gómez Pinto,
    • R. Kiplin Guy,
    • Thomas L. James
    We have synthesized a series of phenothiazine derivatives, which were used to test the structure-activity relationship of binding to HIV-1 TAR RNA. Variations from our initial compound, 2-acetylphenothiazine, focused on two moieties: ring substitutions and n-alkyl substitutions. Binding characteristics were ascertained via NMR, principally by saturation transfer difference spectra of the ligand and imino proton resonance shifts of the RNA. Both ring and alkyl substitutions manifested NMR changes upon binding.
  • A Chemical and Genetic Approach to the Mode of Action of Fumagillin

    • Yi Zhang,
    • Jing Ruey Yeh,
    • Andrew Mara,
    • Rong Ju,
    • John F. Hines,
    • Pasquale Cirone,
    • Hilary L. Griesbach,
    • Igor Schneider,
    • Diane C. Slusarski,
    • Scott A. Holley,
    • Craig M. Crews
    Previous mode of action studies identified methionine aminopeptidase 2 (MetAP-2) as the target of the antiangiogenic natural product fumagillin and its drug candidate analog, TNP-470. We report here that TNP-470-mediated MetAP-2 inhibition blocks noncanonical Wnt signaling, which plays a critical role in development, cell differentiation, and tumorigenesis. Consistent with this finding, antisense MetAP-2 morpholino oligonucleotide injection in zebrafish embryos phenocopies gastrulation defects seen in noncanonical Wnt5 loss-of-function zebrafish mutants.