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51.
Ochi T Wu Q Chirgadze DY Grossmann JG Bolanos-Garcia VM Blundell TL 《Structure (London, England : 1993)》2012,20(7):1212-1222
Knowledge of the architecture of DNA ligase IV (LigIV) and interactions with XRCC4 and XLF-Cernunnos is necessary for understanding its role in the ligation of double-strand breaks during nonhomologous end joining. Here we report the structure of a subdomain of the nucleotidyltrasferase domain of human LigIV and provide insights into the residues associated with LIG4 syndrome. We use this structural information together with the known structures of the BRCT/XRCC4 complex and those of LigIV orthologs to interpret small-angle X-ray scattering of LigIV in complex with XRCC4 and size exclusion chromatography of LigIV, XRCC4, and XLF-Cernunnos. Our results suggest that the flexibility of the catalytic region is limited in a manner that affects the formation of the LigIV/XRCC4/XLF-Cernunnos complex. 相似文献
52.
D Matak-Vinkovi? M Vinkovi? S A Saldanha J L Ashurst F von Delft T Inoue R N Miguel A G Smith T L Blundell C Abell 《Biochemistry》2001,40(48):14493-14500
Ketopantoate reductase (KPR, EC 1.1.1.169) catalyzes the NADPH-dependent reduction of ketopantoate to pantoate on the pantothenate (vitamin B(5)) biosynthetic pathway. The Escherichia coli panE gene encoding KPR was cloned and expressed at high levels as the native and selenomethionine-substituted (SeMet) proteins. Both native and SeMet recombinant proteins were purified by three chromatographic steps, to yield pure proteins. The wild-type enzyme was found to have a K(M)(NADPH) of 20 microM, a K(M)(ketopantoate) of 60 microM, and a k(cat) of 40 s(-1). Regular prismatic KPR crystals were prepared using the hanging drop technique. They belonged to the tetragonal space group P4(2)2(1)2, with cell parameters: a = b = 103.7 A and c = 55.7 A, accommodating one enzyme molecule per asymmetric unit. The structure of KPR was determined by the multiwavelength anomalous dispersion method using the SeMet protein, for which data were collected to 2.3 A resolution. The native data were collected to 1.7 A resolution and used to refine the final structure. The secondary structure comprises 12 alpha-helices, three 3(10)-helices, and 11 beta-strands. The enzyme is monomeric and has two domains separated by a cleft. The N-terminal domain has an alphabeta-fold of the Rossmann type. The C-terminal domain (residues 170-291) is composed of eight alpha-helices. KPR is shown to be a member of the 6-phosphogluconate dehydrogenase C-terminal domain-like superfamily. A model for the ternary enzyme-NADPH-ketopantoate ternary complex provides a rationale for kinetic data reported for specific site-directed mutants. 相似文献
53.
S Patel L Yenush P L Rodríguez R Serrano T L Blundell 《Journal of molecular biology》2002,315(4):677-685
Lithium cations exert profound and selective psychopharmacological effects on ameliorate manic-depressive psychosis. Although lithium is an effective drug for both treatment and prophylaxis of bipolar disorder, the precise mechanism of action is not well understood. Lithium acts as both an uncompetitive and non-competitive inhibitor of several lithium- sensitive phosphatases with regard to substrate and magnesium cofactor, respectively. In this work, we report the crystal structure and reaction mechanism of Rattus norvegicus 3'-phosphoadenosine 5'-phosphate and inositol 1,4-bisphosphate phosphatase (RnPIP), a recently identified target of lithium therapy. This Li(+)-sensitive enzyme plays a crucial role in several cellular processes, such as RNA processing, sulphation reactions and probably inositol recycling. RnPIP specifically removes the 3'-phosphate group of 3'-phosphoadenosine 5'-phosphate (PAP) and the 1'-phosphate group of inositol 1,4-bisphosphate (I(1),(4)P(2)) producing AMP and inositol 4'-phosphate, respectively. The crystal structure of RnPIP complexed with AMP, Pi and magnesium ions at 1.69 A resolution provides insight into the reaction mechanism of the hydrolysis of PAP. The core fold of the enzyme is equivalent to that found in other Li(+)-sensitive phosphatases, such as inositol monophosphatase, but molecular modelling of I(1),(4)P(2) in the RnPIP active site reveals important structural determinants that accommodate this additional substrate. RnPIP is potently inhibited by lithium and, as the accumulation of PAP inhibits a variety of proteins, including sulphotransferases and RNA processing enzymes, this dual specificity enzyme represents a potential target of lithium action, in addition to inositol monophosphatases. 相似文献
54.
Catching a common fold. 总被引:3,自引:2,他引:1
55.
56.
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58.
The TRANSPARENT TESTA GLABRA1 locus, which regulates trichome differentiation and anthocyanin biosynthesis in Arabidopsis, encodes a WD40 repeat protein. 总被引:17,自引:2,他引:15 下载免费PDF全文
59.
Lawrence K. Duffy Michelle K. Hecker Gail M. Blundell R. Terry Bowyer 《Polar Biology》1999,21(1):56-58
Approximately 8 years after the Exxon Valdez oil spill, river otters (Lutra canadensis) were trapped from the shoreline in both oiled (Knight Island) and nonoiled (Jackpot Bay) areas of Prince William Sound,
Alaska. Captive river otters were wiped with isopropanol-soaked gauze and the gauze extracts were analyzed by gas chromatography
with mass spectrometry detection. Differences in pentacosane (C-25) levels in the fur were observed between the oiled and
nonoiled sites, while lower molecular weight aliphatics and aromatics were absent. These data are useful when evaluating the
role of fur grooming in the long-term exposure of river otters to hydrocarbons and the expression of P450-1A in Knight Island
otters.
Accepted: 26 August 1998 相似文献
60.
The acyclic CB1R inverse agonist taranabant mediates weight loss by increasing energy expenditure and decreasing caloric intake 总被引:6,自引:0,他引:6
Addy C Wright H Van Laere K Gantz I Erondu N Musser BJ Lu K Yuan J Sanabria-Bohórquez SM Stoch A Stevens C Fong TM De Lepeleire I Cilissen C Cote J Rosko K Gendrano IN Nguyen AM Gumbiner B Rothenberg P de Hoon J Bormans G Depré M Eng WS Ravussin E Klein S Blundell J Herman GA Burns HD Hargreaves RJ Wagner J Gottesdiener K Amatruda JM Heymsfield SB 《Cell metabolism》2008,7(1):68-78
Cannabinoid 1 receptor (CB1R) inverse agonists are emerging as a potential obesity therapy. However, the physiological mechanisms by which these agents modulate human energy balance are incompletely elucidated. Here, we describe a comprehensive clinical research study of taranabant, a structurally novel acyclic CB1R inverse agonist. Positron emission tomography imaging using the selective CB1R tracer [(18)F]MK-9470 confirmed central nervous system receptor occupancy levels ( approximately 10%-40%) associated with energy balance/weight-loss effects in animals. In a 12-week weight-loss study, taranabant induced statistically significant weight loss compared to placebo in obese subjects over the entire range of evaluated doses (0.5, 2, 4, and 6 mg once per day) (p < 0.001). Taranabant treatment was associated with dose-related increased incidence of clinical adverse events, including mild to moderate gastrointestinal and psychiatric effects. Mechanism-of-action studies suggest that engagement of the CB1R by taranabant leads to weight loss by reducing food intake and increasing energy expenditure and fat oxidation. 相似文献