排序方式: 共有45条查询结果,搜索用时 15 毫秒
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Daniel J. Burkett Brittney N. Wyatt Mallory Mews Anson Bautista Ryan Engel Chris Dockendorff William A. Donaldson Martin St. Maurice 《Bioorganic & medicinal chemistry》2019,27(18):4041-4047
Through a structure-based drug design project (SBDD), potent small molecule inhibitors of pyruvate carboxylase (PC) have been discovered. A series of α-keto acids (7) and α-hydroxycinnamic acids (8) were prepared and evaluated for inhibition of PC in two assays. The two most potent inhibitors were 3,3′-(1,4-phenylene)bis[2-hydroxy-2-propenoic acid] (8u) and 2-hydroxy-3-(quinoline-2-yl)propenoic acid (8v) with IC50 values of 3.0 ± 1.0 μM and 4.3 ± 1.5 μM respectively. Compound 8v is a competitive inhibitor with respect to pyruvate (Ki = 0.74 μM) and a mixed-type inhibitor with respect to ATP, indicating that it targets the unique carboxyltransferase (CT) domain of PC. Furthermore, compound 8v does not significantly inhibit human carbonic anhydrase II, matrix metalloproteinase-2, malate dehydrogenase or lactate dehydrogenase. 相似文献
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Dockendorff TC Su HS McBride SM Yang Z Choi CH Siwicki KK Sehgal A Jongens TA 《Neuron》2002,34(6):973-984
Fragile X mental retardation is a prominent genetic disorder caused by the lack of the FMR1 gene product, a known RNA binding protein. Specific physiologic pathways regulated by FMR1 function have yet to be identified. Adult dfmr1 (also called dfxr) mutant flies display arrhythmic circadian activity and have erratic patterns of locomotor activity, whereas overexpression of dFMR1 leads to a lengthened period. dfmr1 mutant males also display reduced courtship activity which appears to result from their inability to maintain courtship interest. Molecular analysis fails to reveal any defects in the expression of clock components; however, the CREB output is affected. Morphological analysis of neurons required for normal circadian behavior reveals subtle abnormalities, suggesting that defects in axonal pathfinding or synapse formation may cause the observed behavioral defects. 相似文献
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Characterization of dFMR1, a Drosophila melanogaster homolog of the fragile X mental retardation protein 下载免费PDF全文
Fragile X syndrome is the most common inherited form of mental retardation. It is caused by loss of FMR1 gene activity due to either lack of expression or expression of a mutant form of the protein. In mammals, FMR1 is a member of a small protein family that consists of FMR1, FXR1, and FXR2. All three members bind RNA and contain sequence motifs that are commonly found in RNA-binding proteins, including two KH domains and an RGG box. The FMR1/FXR proteins also contain a 60S ribosomal subunit interaction domain and a protein-protein interaction domain which mediates homomer and heteromer formation with each family member. Nevertheless, the specific molecular functions of FMR1/FXR proteins are unknown. Here we report the cloning and characterization of a Drosophila melanogaster homolog of the mammalian FMR1/FXR gene family. This first invertebrate homolog, termed dfmr1, has a high degree of amino acid sequence identity/similarity with the defined functional domains of the FMR1/FXR proteins. The dfmr1 product binds RNA and is similar in subcellular localization and embryonic expression pattern to the mammalian FMR1/FXR proteins. Overexpression of dfmr1 driven by the UAS-GAL4 system leads to apoptotic cell loss in all adult Drosophila tissues examined. This phenotype is dependent on the activity of the KH domains. The ability to induce a dominant phenotype by overexpressing dfmr1 opens the possibility of using genetic approaches in Drosophila to identify the pathways in which the FMR1/FXR proteins function. 相似文献
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Dockendorff TC Robertson SE Faulkner DL Jongens TA 《Molecular & general genetics : MGG》2000,263(1):137-143
We have performed an F2 genetic screen to identify lethal mutations that map to the 44D-45B region of the Drosophila melanogaster genome. By screening 8500 mutagenized chromosomes for lethality over Df(2R)Np3, a deficiency which encompasses nearly 1% of the D. melanogaster euchromatic genome, we recovered 125 lines with lethal mutations that represent 38 complementation groups. The lethal mutations
have been mapped to deficiencies that span the 44D-45B region, producing an approximate map position for each complementation
group. Lethal mutations were analyzed to determine the phase of development at which lethality occurred. In addition, we have
linked some of the complementation groups to P element-induced lethals that map to 44D-45B, thus possibly providing new alleles of a previously tagged gene. Some of the
complementation groups represent potentially novel alleles of previously identified genes that map to the region. Several
genes have been mapped by molecular means to the 44D-45B region, but do not have any reported mutant alleles. This screen
may have uncovered mutant alleles of these genes. The results of complementation tests with previously identified genes in
44D-45B suggests that over half of the complementation groups identified in this screen may be novel.
Received: 13 July 1999 / Accepted: 4 November 1999 相似文献
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Wei-Hsin Chen Ching-Liang Hsieh Chun-Ping Huang Tzu-Jou Lin Jason TC Tzen Tin-Yun Ho Yi-Wen Lin 《Journal of biomedical science》2011,18(1):82
Background
Peripheral tissue inflammation initiates hyperalgesia accompanied by tissue acidosis, nociceptor activation, and inflammation mediators. Recent studies have suggested a significantly increased expression of acid-sensing ion channel 3 (ASIC3) in both carrageenan- and complete Freund's adjuvant (CFA)-induced inflammation. This study tested the hypothesis that acupuncture is curative for mechanical hyperalgesia induced by peripheral inflammation. 相似文献7.
Background
Owing to rapid expansion of protein structure databases in recent years, methods of structure comparison are becoming increasingly effective and important in revealing novel information on functional properties of proteins and their roles in the grand scheme of evolutionary biology. Currently, the structural similarity between two proteins is measured by the root-mean-square-deviation (RMSD) in their best-superimposed atomic coordinates. RMSD is the golden rule of measuring structural similarity when the structures are nearly identical; it, however, fails to detect the higher order topological similarities in proteins evolved into different shapes. We propose new algorithms for extracting geometrical invariants of proteins that can be effectively used to identify homologous protein structures or topologies in order to quantify both close and remote structural similarities. 相似文献8.
Youngsaye W Dockendorff C Vincent B Hartland CL Bittker JA Dandapani S Palmer M Whitesell L Lindquist S Schreiber SL Munoz B 《Bioorganic & medicinal chemistry letters》2012,22(9):3362-3365
Continuing efforts to discover novel means of combating fluconazole resistance in Candida albicans have identified an indole derivative that sensitizes strains demonstrating resistance to fluconazole. This tetracycle (3, ML229) does not appear to act through established Hsp90 or calcineurin pathways to chemosensitize C. albicans, as determined in Saccharomyces cerevisiae models, and may be a useful probe to uncover alternative resistance pathways. 相似文献
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Chris Dockendorff Shujuan Jin Madeline Olsen Mark Lautens Martin Coupal Lejla Hodzic Nathan Spear Kemal Payza Christopher Walpole Mirosław J. Tomaszewski 《Bioorganic & medicinal chemistry letters》2009,19(4):1228-1232
A series of 1-aminotetralin scaffolds was synthesized via metal-catalyzed ring-opening reactions of heterobicyclic alkenes. Small libraries of amides and amines were made using the amino group of each scaffold as a handle. Screening of these libraries against human opioid receptors led to the identification of (S)–(S)-5.2a as a high-affinity selective μ ligand (IC50 μ = 5 nM, κ = 707 nM, δ = 3,795 nM) displaying μ-agonist/antagonist properties due to its partial agonism (EC50 = 2.6 μM; Emax = 18%). 相似文献
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Fuhai Li Xiaobo Zhou Wanting Huang Chung-Che Chang Stephen TC Wong 《BMC bioinformatics》2010,11(1):200