Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor

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• 作者：John S. Sack ; Mian Gao ; Susan E. Kiefer ; Joseph E. Myers Jr ; John A. Newitt ; Sophie Wu and Chunhong Yan
• 关键词：MARK4 ; PAR-1 serine/threonine protein kinase ; transferase
• 刊名：Acta Crystallographica Section F
• 出版年：2016
• 出版时间：February 2016
• 年：2016
• 卷：72
• 期：2
• 页码：129-134
• 全文大小：715K
• ISSN：1744-3091

文摘

Microtubule-associated protein/microtubule affinity-regulating kinase 4 (MARK4) is a serine/threonine kinase involved in the phosphorylation of MAP proteins that regulate microtubule dynamics. Abnormal activity of MARK4 has been proposed to contribute to neurofibrillary tangle formation in Alzheimer's disease. The crystal structure of the catalytic and ubiquitin-associated domains of MARK4 with a potent pyrazolopyrimidine inhibitor has been determined to 2.8 Å resolution with an R_work of 22.8%. The overall structure of MARK4 is similar to those of the other known MARK isoforms. The inhibitor is located in the ATP-binding site, with the pyrazolopyrimidine group interacting with the inter-lobe hinge region while the aminocyclohexane moiety interacts with the catalytic loop and the DFG motif, forcing the activation loop out of the ATP-binding pocket.