期刊名称：SCHOLARLY RESEARCH JOURNAL FOR INTERDISCIPLINARY STUDIES
印刷版ISSN：2319-4766
电子版ISSN：2278-8808
出版年度：2017
卷号：4
期号：37
页码：8890-8908
语种：English
出版社：SCHOLARLY RESEARCH JOURNAL'S
摘要：More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (tyrosine kinase) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with RTK. FLT3 with quizartinib bound adopts an “Abl-like” inactive conformation with the activation loop stabilized in the “DFG-out” orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop.The co-crystal structure reveals the interactions between RTK and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as aFLT3 variant observed.
