Laboratory of Organic Chemistry, ETH Zürich , Zürich CH-8093, Switzerland.
Biochemistry. 2013 Sep 10;52(36):6232-9. doi: 10.1021/bi400838t. Epub 2013 Aug 26.
Glucokinase (GCK) is responsible for maintaining glucose homeostasis in the human body. Dysfunction or misregulation of GCK causes hyperinsulinemia, hypertriglyceridemia, and type 2 diabetes. In the liver, GCK is regulated by interaction with the glucokinase regulatory protein (GKRP), a 68 kDa polypeptide that functions as a competitive inhibitor of glucose binding to GCK. Formation of the mammalian GCK-GKRP complex is stimulated by fructose 6-phosphate and antagonized by fructose 1-phosphate. Here we report the crystal structure of the mammalian GCK-GKRP complex in the presence of fructose 6-phosphate at a resolution of 3.50 Å. The interaction interface, which totals 2060 Å(2) of buried surface area, is characterized by a small number of polar contacts and substantial hydrophobic interactions. The structure of the complex reveals the molecular basis of disease states associated with impaired regulation of GCK by GKRP. It also offers insight into the modulation of complex stability by sugar phosphates. The atomic description of the mammalian GCK-GKRP complex provides a framework for the development of novel diabetes therapeutic agents that disrupt this critical macromolecular regulatory unit.
葡萄糖激酶（GCK）负责维持人体的葡萄糖内稳态。GCK 的功能障碍或调控失常会导致高胰岛素血症、高三酰甘油血症和 2 型糖尿病。在肝脏中，GCK 通过与葡萄糖激酶调节蛋白（GKRP）相互作用来调节，GKRP 是一种 68kDa 的多肽，作为葡萄糖与 GCK 结合的竞争性抑制剂发挥作用。哺乳动物 GCK-GKRP 复合物的形成受果糖 6-磷酸的刺激，受果糖 1-磷酸的拮抗。在这里，我们报道了在存在果糖 6-磷酸的情况下哺乳动物 GCK-GKRP 复合物的晶体结构，分辨率为 3.50Å。相互作用界面总计 2060Ų的埋入表面面积，其特征是极性接触较少，疏水性相互作用较大。该复合物的结构揭示了与 GKRP 对 GCK 调节受损相关的疾病状态的分子基础。它还提供了对糖磷酸调节复合物稳定性的深入了解。哺乳动物 GCK-GKRP 复合物的原子描述为开发破坏这一关键的大分子调节单元的新型糖尿病治疗药物提供了框架。
