4JBQ

Novel Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules

4JBQ の概要

• エントリーDOI: 10.2210/pdb4jbq/pdb
• 関連するPDBエントリー: 4JBO 4JBQ
• 分子名称: Aurora Kinase A, CYCLOPROPANECARBOXYLIC ACID {4-[4-(4-METHYL-PIPERAZIN-1-YL)-6-(5-METHYL-2H-PYRAZOL-3-YLAMINO)-PYRIMIDIN-2-YLSULFANYL]-PHENYL}-AMIDE (3 entities in total)
• 機能のキーワード: aurora kinase inhibitors, hurp, mitotic spindle, transferase
• 由来する生物種: Homo sapiens (human)
• 細胞内の位置: Cytoplasm, cytoskeleton, centrosome: O14965
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 32823.71

構造登録者

Wu, J.S.,Leou, J.S.,Peng, Y.H.,Hsueh, C.C.,Hsieh, H.P.,Wu, S.Y. (登録日: 2013-02-20, 公開日: 2013-06-05, 最終更新日: 2024-03-20)

主引用文献

Wu, J.M.,Chen, C.T.,Coumar, M.S.,Lin, W.H.,Chen, Z.J.,Hsu, J.T.,Peng, Y.H.,Shiao, H.Y.,Lin, W.H.,Chu, C.Y.,Wu, J.S.,Lin, C.T.,Chen, C.P.,Hsueh, C.C.,Chang, K.Y.,Kao, L.P.,Huang, C.Y.,Chao, Y.S.,Wu, S.Y.,Hsieh, H.P.,Chi, Y.H.
Aurora kinase inhibitors reveal mechanisms of HURP in nucleation of centrosomal and kinetochore microtubules.
Proc.Natl.Acad.Sci.USA, 110:E1779-E1787, 2013

PubMed Abstract: The overexpression of Aurora kinases in multiple tumors makes these kinases appealing targets for the development of anticancer therapies. This study identified two small molecules with a furanopyrimidine core, IBPR001 and IBPR002, that target Aurora kinases and induce a DFG conformation change at the ATP site of Aurora A. Our results demonstrate the high potency of the IBPR compounds in reducing tumorigenesis in a colorectal cancer xenograft model in athymic nude mice. Human hepatoma up-regulated protein (HURP) is a substrate of Aurora kinase A, which plays a crucial role in the stabilization of kinetochore fibers. This study used the IBPR compounds as well as MLN8237, a proven Aurora A inhibitor, as chemical probes to investigate the molecular role of HURP in mitotic spindle formation. These compounds effectively eliminated HURP phosphorylation, thereby revealing the coexistence and continuous cycling of HURP between unphosphorylated and phosphorylated forms that are associated, respectively, with microtubules emanating from centrosomes and kinetochores. Furthermore, these compounds demonstrate a spatial hierarchical preference for HURP in the attachment of microtubules extending from the mother to the daughter centrosome. The finding of inequality in the centrosomal microtubules revealed by these small molecules provides a versatile tool for the discovery of new cell-division molecules for the development of antitumor drugs.

PubMed: 23610398
DOI: 10.1073/pnas.1220523110

実験手法

X-RAY DIFFRACTION (2.3 Å)