Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: HUMANGGP:002116 (ACS)
 78,058 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because of analytical limitations, multiple animals or plants are typically required to identify natural products. Using a unique 1-mm high-temperature superconducting NMR probe, we directly examined the chemical composition of defensive secretions from walking stick insects. Individual milkings were dissolved in D2O without purification and examined by NMR within 10 min of secretion. We found that Anisomorpha buprestoides secretes similar quantities of glucose and mixtures of monoterpene dialdehydes that are stereoisomers of dolichodial. Different individual animals produce different stereoisomeric mixtures, the ratio of which varies between individual animals raised in the same container and fed the same food. Another walking stick, Peruphasma schultei, also secretes glucose and a single, unique stereoisomer that we are naming "peruphasmal". These observations suggest a previously unrecognized significance of aqueous components in walking stick defensive sprays. Single-insect variability of venom demonstrates the potential importance of chemical biodiversity at the level of individual animals.
ACS Chem Biol 2006 Sep 19
PMID:Single insect NMR: A new tool to probe chemical biodiversity. 1716 38

Activation of the signal transducer and activator of transcription 3 (STAT3) is frequently detected in many cancer types. Activated STAT3 may participate in oncogenesis by stimulating cell proliferation and resisting apoptosis, as well as promoting tumor angiogenesis, invasion, and migration. Many STAT3-dependent cellular responses are mediated through interactions with other proteins, and the amino-terminal domain (N-domain) of STAT3 was proposed to be responsible for this. Our NMR studies revealed that synthetic analogs of the STAT4 second alpha-helix bind to the N-domain and perturb its structure. Structural data available for the STAT4 N-domain was used for the rational design of STAT3 helix 2 analogs with enhanced biological activity. Cell-permeable derivatives of the STAT3 second helix were found to directly and specifically bind to STAT3 but not STAT1 as determined by FRET analysis in cells expressing GFP-STAT3 and GFP-STAT1. Furthermore, they potently induced apoptotic death in breast cancer cells but not normal breast cells or STAT3-deficient fibroblasts. The inhibitors caused significant changes in the mitochondrial potential of cancer cells, leading to cell death. These compounds not only are promising drug candidates but also offer a convenient tool for studying the mechanisms of action of STAT transcription factors and have facilitated our understanding of the crucial role of the N-domain in STAT3 function.
ACS Chem Biol 2007 Dec 21
PMID:Rationally designed inhibitors identify STAT3 N-domain as a promising anticancer drug target. 1815 67

Recent research on the chemistry of natural products from the author's group that led to the receipt of the ACS Ernest Guenther Award in the Chemistry of Natural Products is reviewed. REDOR NMR and synthetic studies established the T-taxol conformation as the bioactive tubulin-binding conformation, and these results were confirmed by the synthesis of compounds which clearly owed their activity or lack of activity to whether or not they could adopt the T-taxol conformation. Similar studies with the epothilones suggest that the current tubulin-binding model needs to be modified. Examples of natural products discovery and biodiversity conservation in Suriname and Madagascar are also presented, and it is concluded that natural products chemistry will continue to make significant contributions to drug discovery.
 ...
PMID:A natural love of natural products. 1845 34

Anion-transport proteins are central to all of physiology, for processes ranging from regulating bone-density, muscle excitability, and blood pressure, to facilitating extreme-acid survival of pathogenic bacteria. 4,4-Diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) has been used as an anion-transport inhibitor for decades. In this study, we demonstrate that polythiourea products derived from DIDS hydrolysis inhibit three different CLC chloride-transport proteins, ClC-ec1, ClC-0, and ClC-Ka, more effectively than DIDS itself. The structures of the five major products were determined by NMR spectroscopy, mass spectrometry, and chemical synthesis. These compounds bind directly to the CLC proteins, as evidenced by the fact that inhibition of ClC-0 occurs only from the intracellular side and inhibition of ClC-Ka is prevented by the point mutation N68D. These polythioureas are the highest affinity inhibitors known for the CLCs and provide a new class of chemical probes for dissecting the molecular mechanisms of chloride transport.
ACS Chem Biol 2008 Jul 18
PMID:Discovery of potent CLC chloride channel inhibitors. 1864 99

A new synthetic method allows incorporation of 13C or 15N into selected positions within purine nucleotide bases, starting from simple labeled precursors. The procedure harnesses diverse enzymes to support biosynthesis by the pentose phosphate and de novo purine pathways. Selective isotope incorporation should expand the range of RNAs that are amenable to NMR analysis.
ACS Chem Biol 2008 Aug 15
PMID:The purine machine scores a base hit. 1870 57

A general method for isotopic labeling of the purine base moiety of nucleotides and RNA has been developed through biochemical pathway engineering in vitro. A synthetic scheme was designed and implemented utilizing recombinant enzymes from the pentose phosphate and de novo purine synthesis pathways, with regeneration of folate, aspartate, glutamine, ATP, and NADPH cofactors, in a single-pot reaction. Syntheses proceeded quickly and efficiently in comparison to chemical methods with isolated yields up to 66% for 13C-, 15N-enriched ATP and GTP. The scheme is robust and flexible, requiring only serine, NH4+, glucose, and CO2 as stoichiometric precursors in labeled form. Using this approach, U-13C- GTP, U-13C, 15N- GTP, 13C 2,8- ATP, and U-15N- GTP were synthesized on a millimole scale, and the utility of the isotope labeling is illustrated in NMR spectra of HIV-2 transactivation region RNA containing 13C 2,8-adenosine and 15N 1,3,7,9,2-guanosine. Pathway engineering in vitro permits complex synthetic cascades to be effected, expanding the applicability of enzymatic synthesis.
ACS Chem Biol 2008 Aug 15
PMID:Pathway engineered enzymatic de novo purine nucleotide synthesis. 1870 56

The ability to incorporate chemical probes into peptides is of great importance because it can render novel functionality to proteins and greatly expand our capacity to investigate complex biological systems. A methodology developed by the Schultz laboratory provides a unique strategy to incorporate chemical probes as unnatural amino acids into proteins by "expanding the genetic code" of the host cell. A recent application of this methodology that allows the site-specific incorporation of three NMR-active probes into proteins demonstrates the potential for researchers to explore avenues that are not easily achievable with existing methods.
ACS Chem Biol 2008 Sep 19
PMID:Site-specific incorporation of chemical probes into proteins for NMR. 1880 68

Infection by the mosquito-borne dengue virus causes dengue fever and the sometimes fatal dengue hemorrhagic fever. The increasing number of dengue infections per year suggests that the virus is becoming more virulent and its transmission is expanding. Nevertheless, no effective treatment for dengue infection currently exists. In a search for antiviral agents effective against dengue virus, we investigated the potential of targeting a structural protein site rather than an enzymatic one. Using this approach, we now report the discovery of a small molecule ligand that inhibits viral growth. Our results also provide the first evidence that the binding site, a pocket located at the hinge between domains 1 and 2 of the envelope protein (E protein) on the virus surface, is a valid target for antiviral therapy. Ligand candidates were identified from libraries of approximately 142,000 compounds using a computational high-throughput screening protocol targeting this pocket of the E protein. Cell-based assays were conducted on 23 top-ranked compounds. Among four with good antiviral activity profiles, the compound P02 was found to inhibit viral reproduction at micromolar concentrations. Using saturation transfer difference NMR spectroscopy, we also show that the compound binds virus and competes for binding E protein with the known ligand N-octyl-beta-D-glucoside. Together, the results are consistent with an inhibition mechanism against maturation or host-cell entry mediated by ligand binding to the E-protein pocket. P02 is a promising lead compound for future development of an effective treatment against dengue virus and related flaviviruses.
ACS Chem Biol 2008 Dec 19
PMID:Antiviral compounds discovered by virtual screening of small-molecule libraries against dengue virus E protein. 1905 43

P19INK4d consists of five ankyrin repeats and controls the human cell cycle by inhibiting the cyclin D-dependent kinases 4 and 6. Posttranslational phosphorylation of p19INK4d has been described for Ser66 and Ser76. In the present study we show that mimicking the phosphorylation site of p19INK4d by a glutamate substitution at position 76 dramatically decreases the stability of the native but not an intermediate state. At body temperature the native conformation is completely lost and p19INK4d molecules exhibit the intermediate state as judged by kinetic and equilibrium analysis. High resolution NMR spectroscopy verified that the three C-terminal repeats remained folded in the intermediate state, whereas all cross-peaks of the two N-terminal repeats lost their native chemical shift. Molecular dynamic simulations of p19INK4d in different phosphorylation states revealed large-scale motions in phosphorylated p19INK4d, which cause destabilization of the interface between the second and third ankyrin repeat. Only doubly phosphorylated p19INK4d mimic mutants showed in vitro an increased accessibility for ubiquitination, which might be the signal for degradation in vivo.
ACS Chem Biol 2009 Jan 16
PMID:Conformational switch upon phosphorylation: human CDK inhibitor p19INK4d between the native and partially folded state. 1906 2

A marine natural product extract library has been screened with a functional cell-based G-protein coupled receptor assay to find compounds capable of binding the human cannabinoid receptors CB1 and CB2. The methanol extract of the marine sponge Dasychalina fragilis collected in Papua New Guinea was active in the assay. Bioassay-guided fractionation of the extract identified the phosphorylated sterol sulfate haplosamate A (1) as a cannabinoid receptor agonist. The high water solubility of haplosamate A (1) allowed exploration of its binding interactions with the human cannabinoid receptors in whole insect cells by means of saturation transfer double-difference NMR spectroscopy. This technique confirmed that haplosamate A (1) binds selectively to these receptors.
ACS Chem Biol 2009 Feb 20
PMID:Functional cell-based screening and saturation transfer double-difference NMR have identified haplosamate A as a cannabinoid receptor agonist. 1917 6


1 2 3 4 5 6 7 8 9 10 Next >>