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81.
Jennifer M. Kavran Matthew D. Ward Oyindamola O. Oladosu Sabin Mulepati Daniel J. Leahy 《The Journal of biological chemistry》2010,285(32):24584-24590
Hedgehog (Hh) signaling proteins stimulate cell proliferation, differentiation, and tissue patterning at multiple points in animal development. A single Hh homolog is present in Drosophila, but three Hh homologs, Sonic Hh, Indian Hh, and Desert Hh, are present in mammals. Distribution, movement, and reception of Hh signals are tightly regulated, and abnormal Hh signaling is associated with developmental defects and cancer. In addition to the integral membrane proteins Patched and Smoothened, members of the Drosophila Ihog family of adhesion-like molecules have recently been shown to bind Hh proteins with micromolar affinity and positively regulate Hh signaling. Cell adhesion molecule-related, down-regulated by oncogenes (CDO) and Brother of CDO (BOC) are the closest mammalian relatives of Drosophila Ihog, and CDO binds Sonic Hh with micromolar affinity and positively regulates Hh signaling. Despite these similarities, structural and biochemical studies have shown that Ihog and CDO utilize nonorthologous domains and completely different binding modes to interact with cognate Hh proteins. We report here biochemical and x-ray structural studies of Sonic, Indian, and Desert Hh proteins both alone and complexed with active domains of CDO and BOC. These results show that all mammalian Hh proteins bind CDO and BOC in the same manner. We also show that interactions between Hh proteins and CDO are weakened at low pH. Formation of Hh-mediated Hh oligomers is thought to be an important feature of normal Hh signaling, but no conserved self-interaction between Hh proteins is apparent from inspection of 14 independent Hh-containing crystal lattices. 相似文献
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Buckley GM Cooper N Dyke HJ Galleway FP Gowers L Haughan AF Kendall HJ Lowe C Maxey R Montana JG Naylor R Oxford J Peake JC Picken CL Runcie KA Sabin V Sharpe A Warneck JB 《Bioorganic & medicinal chemistry letters》2002,12(12):1613-1615
A series of bicyclic heteroaryl ring systems was considered as a replacement for the 3-cyclopentyloxy-4-methoxyphenyl moiety in rolipram resulting in the discovery of 8-methoxyquinoline-5-carboxamides as potent inhibitors of phosphodiesterase type 4 (PDE4). 相似文献
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Joseph Guiles Xicheng Sun Ian A. Critchley Urs Ochsner Ming Tregay Kim Stone Jennifer Bertino Louis Green Rob Sabin Frank Dean H. Garry Dallmann Charles S. McHenry Nebojsa Janjic 《Bioorganic & medicinal chemistry letters》2009,19(3):800-802
High throughput screening led to the discovery of a novel series of quinazolin-2-ylamino-quinazolin-4-ols as a new class of DNA polymerase III inhibitors. The inhibition of chromosomal DNA replication results in bacterial cell death. The synthesis, structure–activity relationships and functional activity are described. 相似文献
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Buckley GM Ceska TA Fraser JL Gowers L Groom CR Higueruelo AP Jenkins K Mack SR Morgan T Parry DM Pitt WR Rausch O Richard MD Sabin V 《Bioorganic & medicinal chemistry letters》2008,18(11):3291-3295
A potent IRAK-4 inhibitor was identified through routine project cross screening. The binding mode was inferred using a combination of in silico docking into an IRAK-4 homology model, surrogate crystal structure analysis and chemical analogue SAR. 相似文献
89.
Ellen J. Coombs Rob Deaville Richard C. Sabin Louise Allan Mick O'Connell Simon Berrow Brian Smith Andrew Brownlow Mariel Ten Doeschate Rod Penrose Ruth Williams Matthew W. Perkins Paul D. Jepson Natalie Cooper 《Marine Mammal Science》2019,35(4):1527-1555
There are many factors that may explain why cetaceans (whales, dolphins, and porpoises) strand. Around the UK and Ireland, over 20,000 stranding records have been collected since 1913, resulting in one of the longest, continuous, systematic stranding data sets in the world. We use this data set to investigate temporal and spatial trends in cetacean strandings and use generalized additive models (GAMs) to investigate correlates of strandings. We find a dramatic increase in strandings since the 1980s, most likely due to increases in recording effort, and the formation of formal strandings networks. We found no correlation between the numbers of cetaceans stranding each year and several potential environmental and anthropogenic predictors: storms, geomagnetic activity, North Atlantic Oscillations, sea‐surface temperature, and fishing catch. We suggest that this is because the scale of change in the variables is too coarse to detect any potential correlations. It may also highlight the idiosyncratic nature of species’ responses to external pressures, and further the need to investigate other potential correlates of strandings, such as bycatch and military sonar. Long‐term cetacean stranding data provide vital information on past and present diversity for common, rare, and inconspicuous species. This study underlines the importance of continued support for stranding networks. 相似文献