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Crystal structure of microtubule affinity‐regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor
Author(s) -
Sack John S.,
Gao Mian,
Kiefer Susan E.,
Myers Joseph E.,
Newitt John A.,
Wu Sophie,
Yan Chunhong
Publication year - 2016
Publication title -
acta crystallographica section f
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.572
H-Index - 37
ISSN - 2053-230X
DOI - 10.1107/s2053230x15024747
Subject(s) - kinase , microtubule , serine , chemistry , protein kinase domain , threonine , transferase , phosphorylation , cooperativity , microbiology and biotechnology , biochemistry , biology , biophysics , enzyme , mutant , gene
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.