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The prediction of a protein's tertiary structure is still a considerable problem because the huge amount of possible conformational space1 makes it computationally difficult. With regard to side-chain modelling, a solution has been attempted by the grouping of side-chain conformations into representative sets of rotamers2??. Nonetheless, an exhaustive combinatorial search is still limited to carefully indentified packing units?? containing a limited number of residues. For larger systems other strategies had to be developed, such as the Monte Carlo Procedure?? and the genetic algorithm and clustering approach?. Here we present a theorem, referred to as the 'dead-end elimination' theorem, which imposes a suitable condition to identify rotamers that cannot be members of the global minimum energy conformation. Application of this theorem effectively controls the computational explosion of the rotamer combinatorial problem, thereby allowing the determination of the global minimum energy conformation of a large collection of side chains. 相似文献
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Increasing evidence implies altered signaling through the neurotrophic receptor tyrosine kinase TrkB in promoting tumor formation
and metastasis. TrkB, sometimes in conjunction with its primary ligand BDNF, is often overexpressed in a variety of human
cancers, ranging from neuroblastomas to pancreatic ductal adenocarcinomas, in which it may allow tumor expansion and contribute
to resistance to anti-tumor agents. In vitro, TrkB acts as a potent suppressor of anoikis (detachment-induced apoptosis), which is associated with the acquisition of
an aggressive tumorigenic and metastatic phenotype in vivo. In view of its predicted contribution to tumorigenicity and metastasis in humans, TrkB corresponds to a potential drug target,
and preclinical models have already been established. The encouraging results of pharmacological Trk inhibitors in tumor xenograft
models suggest that TrkB inhibition may represent a promising novel anti-tumor therapeutic strategy. This hypothesis is currently
being evaluated in clinical trials. Here, we will discuss the latest developments on TrkB in these contexts as well as highlight
some critical questions that remain to be addressed for evaluating TrkB as a therapeutic target in cancer.
Received 12 October 2005; received after revision 19 December 2005; accepted 11 January 2006 相似文献
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Résumé La capacité de transport de la bilirubine dans le foie de rat a été mesurée par différents auteurs. Dans nos expériments leT
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était variable selon les conditions expérimentales. En stabilisant la température à 38 C pendant les 10 h qui suivent l'opération, le Tm s'avère 50% plus élevé que les valeurs données dans la littérature. En plus la valeur du Tm était étroitement correlée au débit biliaire. 相似文献
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Lambrechts D Storkebaum E Morimoto M Del-Favero J Desmet F Marklund SL Wyns S Thijs V Andersson J van Marion I Al-Chalabi A Bornes S Musson R Hansen V Beckman L Adolfsson R Pall HS Prats H Vermeire S Rutgeerts P Katayama S Awata T Leigh N Lang-Lazdunski L Dewerchin M Shaw C Moons L Vlietinck R Morrison KE Robberecht W Van Broeckhoven C Collen D Andersen PM Carmeliet P 《Nature genetics》2003,34(4):383-394
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