University of Tromsø, Norway.
Cell Mol Life Sci. 2011 Jan;68(2):289-301. doi: 10.1007/s00018-010-0452-1. Epub 2010 Jul 17.
The mitogen-activated protein kinase-activated protein kinase MK5 is ubiquitously expressed in vertebrates and is implicated in cell proliferation, cytoskeletal remodeling, and anxiety behavior. This makes MK5 an attractive drug target. We tested several diterpenoid alkaloids for their ability to suppress MK5 kinase activity. We identified noroxoaconitine as an ATP competitor that inhibited the catalytic activity of MK5 in vitro (IC₅₀ = 37.5 μM; K(i) = 0.675 μM) and prevented PKA-induced nuclear export of MK5, a process that depends on kinase active MK5. MK5 is closely related to MK2 and MK3, and noroxoaconitine inhibited MK3- and MK5- but not MK2-mediated phosphorylation of the common substrate Hsp27. Molecular docking of noroxoaconitine into the ATP binding sites indicated that noroxoaconitine binds more strongly to MK5 than to MK3. Noroxoaconitine and derivatives may help in elucidating the precise biological functions of MK5 and may prove to have therapeutic values.
丝裂原活化蛋白激酶激活的蛋白激酶 MK5 在脊椎动物中广泛表达，与细胞增殖、细胞骨架重塑和焦虑行为有关。这使得 MK5 成为一个有吸引力的药物靶点。我们测试了几种二萜生物碱抑制 MK5 激酶活性的能力。我们发现去氧乌头碱是一种 ATP 竞争抑制剂，可在体外抑制 MK5 的催化活性（IC₅₀=37.5μM；K(i)=0.675μM），并阻止 PKA 诱导的 MK5 核输出，这一过程依赖于具有激酶活性的 MK5。MK5 与 MK2 和 MK3 密切相关，去氧乌头碱抑制 MK3 和 MK5 介导的共同底物 Hsp27 的磷酸化，但不抑制 MK2 介导的磷酸化。去氧乌头碱与 ATP 结合位点的分子对接表明，去氧乌头碱与 MK5 的结合比与 MK3 的结合更强。去氧乌头碱及其衍生物可能有助于阐明 MK5 的精确生物学功能，并可能具有治疗价值。
