title: Structure of the β-form of human MK2 in complex with the non-selective kinase inhibitor TEI-L03090.
abstract: Mitogen-activated protein kinase-activated protein kinase 2 (MK2 or MAPKAP-K2), a serine/threonine kinase from the p38 mitogen-activated protein kinase signalling pathway, plays an important role in the production of TNF-α and other cytokines. In a previous report, it was shown that MK2 in complex with the selective inhibitor TEI-I01800 adopts an α-helical glycine-rich loop that is induced by the stable nonplanar conformer of TEI-I01800. To understand the mechanism of the structural change, the structure of MK2 bound to TEI-L03090, which lacks the key substituent found in TEI-I01800, was determined. MK2-TEI-L03090 has a β-sheet glycine-rich loop in common with other kinases, as predicted. This result suggests that a small compound can induce a drastic conformational change in the target protein structure and can be used to design potent and selective inhibitors.
authors: Teijin Institute for Bio-medical Research, Teijin Pharma Ltd, 4-3-2 Asahigaoka, Hino-shi, Tokyo 191-8512, Japan.
authors: Aiko
authors: A
authors: Fujino
authors: Kei
authors: K
authors: Fukushima
authors: Takaharu
authors: T
authors: Kubota
authors: Yoshiyuki
authors: Y
authors: Matsumoto
authors: Midori
authors: M
authors: Takimoto-Kamimura
mesh_terms: D000595:Amino Acid Sequence; D018360:Crystallography, X-Ray; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D047428:Protein Kinase Inhibitors / Q000737:chemistry*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D011720:Pyrazoles / Q000737:chemistry*; D011743:Pyrimidines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D040681:Structural Homology, Protein; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D006575:Heterocyclic Compounds, 3-Ring; D047908:Intracellular Signaling Peptides and Proteins; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011720:Pyrazoles; D011743:Pyrimidines; D011994:Recombinant Proteins; D000099190:MAP-Kinase-Activated Kinase 2; C550248:TEI I01800; C000589980:TEI-L03090
keywords: MAPKAP-K2; MK2; conformational change; glycine-rich loop; inhibitors