| 16672372 |
Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors |
10.1073/pnas.0510284103. |
Proc Natl Acad Sci U S A |
Epidermal growth factor receptor variant III mutations in lung tumorigenesis and sensitivity to tyrosine kinase inhibitors
Abstract
- The tyrosine kinase inhibitors gefitinib (Iressa) and erlotinib (Tarceva) have shown anti-tumor activity in the treatment of non-small cell lung cancer (NSCLC). Dramatic and durable responses have occurred in NSCLC tumors with mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR). In contrast, these inhibitors have shown limited efficacy in glioblastoma, where a distinct EGFR mutation, the variant III (vIII) in-frame deletion of exons 2-7, is commonly found. In this study, we determined that EGFRvIII mutation was present in 5% (3/56) of analyzed human lung squamous cell carcinoma (SCC) but was not present in human lung adenocarcinoma (0/123). We analyzed the role of the EGFRvIII mutation in lung tumorigenesis and its response to tyrosine kinase inhibition. Tissue-specific expression of EGFRvIII in the murine lung led to the development of NSCLC. Most importantly, these lung tumors depend on EGFRvIII expression for maintenance. Treatment with an irreversible EGFR inhibitor, HKI-272, dramatically reduced the size of these EGFRvIII-driven murine tumors in 1 week. Similarly, Ba/F3 cells transformed with the EGFRvIII mutant were relatively resistant to gefitinib and erlotinib in vitro but proved sensitive to HKI-272. These findings suggest a therapeutic strategy for cancers harboring the EGFRvIII mutation.
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| 16689926 |
alpha-Conotoxin GI benzoylphenylalanine derivatives. (1)H-NMR structures and photoaffinity labeling of the Torpedo californica nicotinic acetylcholine receptor |
10.1111/j.1742-4658.2006.05161.x. |
FEBS J |
alpha-Conotoxin GI benzoylphenylalanine derivatives. (1)H-NMR structures and photoaffinity labeling of the Torpedo californica nicotinic acetylcholine receptor
Abstract
- alpha-Conotoxins are small peptides from cone snail venoms that function as nicotinic acetylcholine receptor (nAChR)-competitive antagonists differentiating between nAChR subtypes. Current understanding about the mechanism of these selective interactions is based largely on mutational analyses, which identify amino acids in the toxin and nAChR that determine the energetics of ligand binding. To identify regions of the nAChR involved in alpha-conotoxin binding by use of photoactivated cross-linking, two benzoylphenylalanine (Bpa) analogs of alpha-conotoxin GI, GI(Bpa12) and GI(Bpa4), were synthesized by replacing the respective residues with Bpa, and their (1)H-NMR structures were determined. Both analogs preserved the GI conformation, but only GI(Bpa12) displaced (125)I-labeled GI from the Torpedo californica nAChR. (125)I-labeled GI(Bpa12) bound to two sites on the receptor (K(d) 13 and 1800 nM), and on UV irradiation specifically photolabeled the alpha, gamma and delta subunits. Photolabeling sites were mapped by selective proteolysis and enzymatic deglycosylation, combined with SDS/PAGE, HPLC and Edman degradation. In the alpha subunit, cobratoxin-inhibited incorporation was limited to the 22-kDa fragment beginning at alphaSer173 and containing the agonist-binding site segment C. In the gamma subunit, radioactivity was localized to two distinct peptides containing agonist-binding site segments F and D: nonglycosylated 24-kDa and glycosylated 13-kDa fragments starting at gammaAla167 and gammaAla49, respectively. The labeling of these fragments is discussed in terms of a model of GI(Bpa12) bound to the extracellular domain of the Torpedo nAChR homology model derived from the cryo-electron microscopy structure of Torpedo marmorata nAChR and X-ray crystal structures of snail acetylcholine-binding protein complexes with agonists and antagonists.
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| 16697012 |
Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site |
10.1016/j.jmb.2006.04.005. |
J Mol Biol |
Structure of the human multidrug resistance protein 1 nucleotide binding domain 1 bound to Mg2+/ATP reveals a non-productive catalytic site
Abstract
- Human multidrug resistance protein 1 (MRP1) is a membrane protein that belongs to the ATP-binding cassette (ABC) superfamily of transport proteins. MRP1 contributes to chemotherapy failure by exporting a wide range of anti-cancer drugs when over expressed in the plasma membrane of cells. Here, we report the first high-resolution crystal structure of human MRP1-NBD1. Drug efflux requires energy resulting from hydrolysis of ATP by nucleotide binding domains (NBDs). Contrary to the prokaryotic NBDs, the extremely low intrinsic ATPase activity of isolated MRP1-NBDs allowed us to obtain the structure of wild-type NBD1 in complex with Mg2+/ATP. The structure shows that MRP1-NBD1 adopts a canonical fold, but reveals an unexpected non-productive conformation of the catalytic site, providing an explanation for the low intrinsic ATPase activity of NBD1 and new hypotheses on the cooperativity of ATPase activity between NBD1 and NBD2 upon heterodimer formation.
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| 16706541 |
Verpacamides A-D, a sequence of C11N5 diketopiperazines relating cyclo(Pro-Pro) to cyclo(Pro-Arg), from the marine sponge Axinella vaceleti: possible biogenetic precursors of pyrrole-2-aminoimidazole alkaloids |
10.1021/ol0608092. |
Org Lett |
Verpacamides A-D, a sequence of C11N5 diketopiperazines relating cyclo(Pro-Pro) to cyclo(Pro-Arg), from the marine sponge Axinella vaceleti: possible biogenetic precursors of pyrrole-2-aminoimidazole alkaloids
Abstract
- [reaction: see text] Four C(11)N(5) diketopiperazine metabolites named verpacamides A (6), B (7), C (8), and D (9) consisting of a proline-arginine dipeptide skeleton have been isolated from the marine sponge Axinella vaceleti. Verpacamides A-D are a sequence of metabolites showing the transformation of proline and arginine into the oxidized guanidinyl-cyclo(Pro-Pro) 8 and 9. Compounds 6-9 are structurally and chemically related to C(11)N(5) pyrrole-2-aminoimidazole metabolites also isolated from the Axinellidae and Agelasidae families of sponges and exemplified by dispacamide A (4) and dibromophakellin (10).
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| 16710414 |
The DNA sequence and biological annotation of human chromosome 1 |
10.1038/nature04727 |
Nature |
The DNA sequence and biological annotation of human chromosome 1
Abstract
- The reference sequence for each human chromosome provides the framework for understanding genome function, variation and evolution. Here we report the finished sequence and biological annotation of human chromosome 1. Chromosome 1 is gene-dense, with 3,141 genes and 991 pseudogenes, and many coding sequences overlap. Rearrangements and mutations of chromosome 1 are prevalent in cancer and many other diseases. Patterns of sequence variation reveal signals of recent selection in specific genes that may contribute to human fitness, and also in regions where no function is evident. Fine-scale recombination occurs in hotspots of varying intensity along the sequence, and is enriched near genes. These and other studies of human biology and disease encoded within chromosome 1 are made possible with the highly accurate annotated sequence, as part of the completed set of chromosome sequences that comprise the reference human genome.
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| 16713657 |
Lividins: novel antimicrobial peptide homologs from the skin secretion of the Chinese Large Odorous frog, Rana (Odorrana) livida. Identification by "shotgun" cDNA cloning and sequence analysis |
10.1016/j.peptides.2006.04.007. |
Peptides |
Lividins: novel antimicrobial peptide homologs from the skin secretion of the Chinese Large Odorous frog, Rana (Odorrana) livida. Identification by "shotgun" cDNA cloning and sequence analysis
Abstract
- Odorous frogs of the sub-genus Odorrana are of oriental distribution, and are so called due to the foul smell of their defensive skin secretions released from specialized skin glands following stress or predator attack. Here we report the application of a "shotgun" skin secretion cDNA library cloning technique which can rapidly expedite identification of secretion bioactive peptides. From a library constructed from the skin secretion of the Large Chinese Odorous frog, Rana (Odorrana) livida, we have identified four novel peptides whose primary structures were deduced initially from cloned precursors. Subsequently, mature peptides were located in and structurally characterized from reverse phase HPLC fractions of skin secretion. Named lividins 1-4, these were found to be structural homologs of known antimicrobial peptide families from Rana frogs. Rapid identification of novel peptides can thus be rapidly achieved using this non-invasive, non-destructive technology and the extensive similarities revealed between antimicrobial peptide precursor organization and nucleic acid sequences would lend support to the hypothesis that they have a common ancestral origin.
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| 16724455 |
FR220897 and FR220899, novel antifungal lipopeptides from Coleophoma empetri no. 14573 |
10.1038/ja.2006.22. |
J Antibiot (Tokyo) |
FR220897 and FR220899, novel antifungal lipopeptides from Coleophoma empetri no. 14573
Abstract
- Novel antifungal lipopeptides, FR220897 and FR220899, were isolated from the fermentation broth of a fungal strain No. 14573. This strain was identified as Coleophoma empetri No. 14573 from morphological and physiological characteristics. FR220897 and FR220899 showed antifungal activities against Aspergillus fumigatus and Candida albicans attributed to inhibition of 1,3-beta-glucan synthesis. Furthermore, FR220897 was effective in a murine model of systemic candidiasis.
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| 16724456 |
FR227673 and FR190293, novel antifungal lipopeptides from Chalara sp. No. 22210 and tolypocladium parasiticum No. 16616 |
10.1038/ja.2006.23. |
J Antibiot (Tokyo) |
FR227673 and FR190293, novel antifungal lipopeptides from Chalara sp. No. 22210 and tolypocladium parasiticum No. 16616
Abstract
- Novel antifungal lipopeptides, FR227673 and FR190293, were isolated from the fermentation broths of fungal strains Chalara sp. No. 22210 and Tolypocladium parasiticum No. 16616, respectively. These compounds have the same cyclic peptide nuclear structure as FR901379, with different side chains, and showed antifungal activity against Aspergillus fumigatus and Candida albicans attributed to inhibition of 1,3-beta-glucan synthesis.
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| 16724845 |
Antineoplastic Agents. 554. The manitoba bacterium Streptomyces sp |
10.1021/np058087v. |
J Nat Prod |
Antineoplastic Agents. 554. The manitoba bacterium Streptomyces sp
Abstract
- A Streptomyces sp. isolated from riverbank soil in Manitoba, Canada, was found to contain two cancer cell growth inhibitories: diazaanthraqui 1 and 3-(hydroxyacetyl)indole (8). The structures were determined by interpretation of data from HRMS, UV, and high-field (400 MHz) NMR experiments. The red-colored diazaanthraqui 1 and 3-(hydroxyacetyl)indole (8) were found to inhibit (0.1-3 microg/mL) growth of a minipanel of human cancer cell lines and P388 lymphocytic leukemia cells. Diazaanthraqui 1 was also found to inhibit growth of the bacteria Streptococcus pneumoniae and Neisseria gonorrheae. However, three companion constituents, cyclo-Pro-Leu (5), cyclo-Pro-Phe (6), and cyclo-Pro-Val (7), did not inhibit cancer cell growth.
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| 16724855 |
Cycloleonuripeptides E and F, cyclic nonapeptides from Leonurus heterophyllus |
10.1021/np050544k. |
J Nat Prod |
Cycloleonuripeptides E and F, cyclic nonapeptides from Leonurus heterophyllus
Abstract
- Two new cyclic nonapeptides, cycloleonuripeptide E, cyclo (-Ala-Pro-Ile-Val-Ala-Ala-Phe-Thr-Pro-), and cycloleonuripeptide F, cyclo (-Gly-Tyr-Pro-Leu-Pro-Phe-Tyr-Pro-Pro-), have been isolated from the fruits of Leonurus heterophyllus, and their structures were elucidated by 2D NMR analysis and chemical degradation. Cycloleonuripeptides E (1) and F (2) showed moderate vasorelaxant effects on rat aorta.
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| 16738124 |
Four psychrotolerant species with high chemical diversity consistently producing cycloaspeptide A, Penicillium jamesonlandense sp. nov., Penicillium ribium sp. nov., Penicillium soppii and Penicillium lanosum |
10.1099/ijs.0.64160-0. |
Int J Syst Evol Microbiol |
Four psychrotolerant species with high chemical diversity consistently producing cycloaspeptide A, Penicillium jamesonlandense sp. nov., Penicillium ribium sp. nov., Penicillium soppii and Penicillium lanosum
Abstract
- Penicillium jamesonlandense is a novel species from Greenland that grows exceptionally slowly at 25 degrees C and has an optimum temperature for growth of 17-18 degrees C. The novel species is more psychrotolerant than any other Penicillium species described to date. Isolates of this novel species produce a range of secondary metabolites with a high chemical diversity, represented by kojic acid, penicillic acid, griseofulvin, pseurotin, chrysogine, tryptoquivalins and cycloaspeptide. Penicillium ribium, another novel psychrotolerant species from the Rocky Mountains, Wyoming, USA, produces asperfuran, kojic acid and cycloaspeptide. Originally reported from an unidentified Aspergillus species isolated from Nepal, cycloaspeptide A is reported here for the first time from the two novel Penicillium species and two known psychrotolerant species with high chemical diversity, Penicillium soppii and Penicillium lanosum. All species, except P. ribium, produce a combination of cycloaspeptide and griseofulvin. However, P. ribium (3/5 strains) produced the precursor to griseofulvin, norlichexanthone. The type strain of Penicillium jamesonlandense sp. nov. is DAOM 234087(T) (=IBT 21984(T) = IBT 24411(T) = CBS 102888(T)) and the type strain of Penicillium ribium sp. nov. is DAOM 234091(T) (=IBT 16537(T) = IBT 24431(T)).
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| 16738553 |
Highly accurate genome sequences of Escherichia coli K-12 strains MG1655 and W3110 |
10.1038/msb4100049 |
Molecular systems biology |
Highly accurate genome sequences of Escherichia coli K-12 strains MG1655 and W3110
Abstract
- With the goal of solving the whole-cell problem with Escherichia coli K-12 as a model cell, highly accurate genomes were determined for two closely related K-12 strains, MG1655 and W3110. Completion of the W3110 genome and comparison with the MG1655 genome revealed differences at 267 sites, including 251 sites with short, mostly single-nucleotide, insertions or deletions (indels) or base substitutions (totaling 358 nucleotides), in addition to 13 sites with an insertion sequence element or defective prophage in only one strain and two sites for the W3110 inversion. Direct DNA sequencing of PCR products for the 251 regions with short indel and base disparities revealed that only eight sites are true differences. The other 243 discrepancies were due to errors in the original MG1655 sequence, including 79 frameshifts, one amino-acid residue deletion, five amino-acid residue insertions, 73 missense, and 17 silent changes within coding regions. Errors in the original MG1655 sequence (<1 per 13,000 bases) were mostly within portions sequenced with out-dated technology based on radioactive chemistry.
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| 16751554 |
Structure of trichamide, a cyclic peptide from the bloom-forming cyanobacterium Trichodesmium erythraeum, predicted from the genome sequence |
10.1128/AEM.00380-06. |
Appl Environ Microbiol |
Structure of trichamide, a cyclic peptide from the bloom-forming cyanobacterium Trichodesmium erythraeum, predicted from the genome sequence
Abstract
- A gene cluster for the biosynthesis of a new small cyclic peptide, dubbed trichamide, was discovered in the genome of the global, bloom-forming marine cyanobacterium Trichodesmium erythraeum ISM101 because of striking similarities to the previously characterized patellamide biosynthesis cluster. The tri cluster consists of a precursor peptide gene containing the amino acid sequence for mature trichamide, a putative heterocyclization gene, an oxidase, two proteases, and hypothetical genes. Based upon detailed sequence analysis, a structure was predicted for trichamide and confirmed by Fourier transform mass spectrometry. Trichamide consists of 11 amino acids, including two cysteine-derived thiazole groups, and is cyclized by an N C terminal amide bond. As the first natural product reported from T. erythraeum, trichamide shows the power of genome mining in the prediction and discovery of new natural products.
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| 16754662 |
The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1 |
10.1074/jbc.M604550200. |
J Biol Chem |
The synthesis, structural characterization, and receptor specificity of the alpha-conotoxin Vc1.1
Abstract
- The alpha-conotoxin Vc1.1 is a small disulfide-bonded peptide currently in development as a treatment for neuropathic pain. This study describes the synthesis, determination of the disulfide connectivity, and the determination of the three-dimensional structure of Vc1.1 using NMR spectroscopy. Vc1.1 was shown to inhibit nicotine-evoked membrane currents in isolated bovine chromaffin cells in a concentration-dependent manner and preferentially targets peripheral nicotinic acetylcholine receptor (nAChR) subtypes over central subtypes. Specifically, Vc1.1 is selective for alpha3-containing nAChR subtypes. The three-dimensional structure of Vc1.1 comprises a small alpha-helix spanning residues Pro6 to Asp11 and is braced by the I-III, II-IV disulfide connectivity seen in other alpha-conotoxins. A comparison of the structure of Vc1.1 with other alpha-conotoxins, taken together with nAChR selectivity data, suggests that the conserved proline at position 6 is important for binding, whereas a number of residues in the C-terminal portion of the peptide contribute toward the selectivity. The structure reported here should open new opportunities for further development of Vc1.1 or analogues as analgesic agents.
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| 16755614 |
Characterization of nodularin variants in Nodularia spumigena from the Baltic Sea using liquid chromatography/mass spectrometry/mass spectrometry |
10.1002/rcm.2558. |
Rapid Commun Mass Spectrom |
Characterization of nodularin variants in Nodularia spumigena from the Baltic Sea using liquid chromatography/mass spectrometry/mass spectrometry
Abstract
- Nodularin is a potent hepatotoxic cyclic pentapeptide produced by planktonic cyanobacterium Nodularia spumigena. Bloom and culture samples of the cyanobacterium collected and isolated from the Gulf of Gdańsk, southern Baltic Sea, were analyzed. Hybrid quadrupole-time-of-flight liquid chromatography/mass spectrometry/mass spectrometry (TOF-LC/MS/MS) with ionspray (ISP) and collision-induced dissociation (CID) were used to characterize nodularin and its analogues. The identification process was based on the comparison of recorded product ion spectra with the previously reported FAB-MS/CID (high-energy) mass spectra of the corresponding nodularin variants. Amino acid structures and sequences were derived from the fragmentation pattern of the [M+H](+) ions. Apart from unmodified nodularin with an arginine residue (NOD-R), three demethylated variants have been found. The sites of demethylation were located on aspartic acid [Asp(1)]NOD, the Adda residue [DMAdda(3)]NOD, and dehydrobutyric acid [dhb(5)]NOD. In two other nodularin variants an additional methyl group is located in the Adda [MeAdda]NOD and Glu [Glu(4)(OMe)]NOD residues. The linear NOD and the geometrical isomer of NOD-R, reported earlier in N. spumigena from New Zealand, have also been detected. Two of the total eight nodularin variants characterized in the present study, [dhb(5)]NOD and [MeAdda]NOD, have not been described earlier.
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