Alexeeva Marina, Åberg Espen, Engh Richard A, Rothweiler Ulli
Department of Chemistry, The Norwegian Structural Biology Centre, The Arctic University of Norway, 9037 Tromsø, Norway.
Acta Crystallogr D Biol Crystallogr. 2015 May;71(Pt 5):1207-15. doi: 10.1107/S1399004715005106. Epub 2015 Apr 25.
Dual-specificity tyrosine phosphorylation-regulated kinase 1A (DYRK1A) is a protein kinase associated with neuronal development and brain physiology. The DYRK kinases are very unusual with respect to the sequence of the catalytic loop, in which the otherwise highly conserved arginine of the HRD motif is replaced by a cysteine. This replacement, along with the proximity of a potential disulfide-bridge partner from the activation segment, implies a potential for redox control of DYRK family activities. Here, the crystal structure of DYRK1A bound to PKC412 is reported, showing the formation of the disulfide bridge and associated conformational changes of the activation loop. The DYRK kinases represent emerging drug targets for several neurological diseases as well as cancer. The observation of distinct activation states may impact strategies for drug targeting. In addition, the characterization of PKC412 binding offers new insights for DYRK inhibitor discovery.
双特异性酪氨酸磷酸化调节激酶1A（DYRK1A）是一种与神经元发育和脑生理学相关的蛋白激酶。DYRK激酶在催化环序列方面非常独特，其中HRD基序中原本高度保守的精氨酸被半胱氨酸取代。这种取代，连同来自激活片段的潜在二硫键伙伴的接近，暗示了DYRK家族活性的氧化还原控制潜力。在此，报道了与PKC412结合的DYRK1A的晶体结构，显示了二硫键的形成以及激活环的相关构象变化。DYRK激酶是几种神经疾病以及癌症新出现的药物靶点。对不同激活状态的观察可能会影响药物靶向策略。此外，PKC412结合的表征为DYRK抑制剂的发现提供了新的见解。
