Crystal structure of microtubule affinity‐regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor. Issue 2 (22nd February 2016)

• Record Type: Journal Article
• Authors: Sack, John S.; Gao, Mian; Kiefer, Susan E.; Myers, Joseph E.; Newitt, John A.; Wu, Sophie; Yan, Chunhong
• Is Part Of: Acta crystallographica. Volume 72:Issue 2(2016:Feb.)
• Page Start: 129
• Page End: 134
• Publication Date: 2016-02-22
• Subjects: MARK4 -- PAR‐1 serine/threonine protein kinase -- transferase; Crystallography -- Periodicals; Crystals -- Periodicals; 548
• DOI: 10.1107/S2053230X15024747
• Languages: English
• ISSNs: 2053-230X

Abstract

Abstract : The crystal structure of the catalytic domain of MARK4 was determined and compared with those of other proteins belonging to the MARK/PAR‐1 protein kinase family. Abstract : 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.