title: Crystal structure of microtubule affinity-regulating kinase 4 catalytic domain in complex with a pyrazolopyrimidine inhibitor.
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 Rwork 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.
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: John S
authors: JS
authors: Sack
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: Mian
authors: M
authors: Gao
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: Susan E
authors: SE
authors: Kiefer
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: Joseph E
authors: JE
authors: Myers
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: John A
authors: JA
authors: Newitt
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: Sophie
authors: S
authors: Wu
authors: Molecular Discovery Technologies, Bristol-Myers Squibb Research and Development, PO Box 4000, Princeton, NJ 08543-4000, USA.
authors: Chunhong
authors: C
authors: Yan
mesh_terms: D000595:Amino Acid Sequence; D003460:Crystallization / Q000379:methods*; D018360:Crystallography, X-Ray / Q000379:methods*; D006801:Humans; D008969:Molecular Sequence Data; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism*; D011720:Pyrazoles / Q000737:chemistry* / Q000378:metabolism*; D011743:Pyrimidines / Q000737:chemistry* / Q000378:metabolism*
chemical_list: D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011743:Pyrimidines; C000606692:pyrazolylpyrimidine; C483047:MARK4 protein, human; D017346:Protein Serine-Threonine Kinases
keywords: MARK4; PAR-1 serine/threonine protein kinase; transferase