Department of Medicinal Chemistry, School of Pharmacy, Virginia Commonwealth University, 800 East Leigh Street, Richmond, VA, 23298, USA.
Department of Human and Molecular Genetics, School of Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA; Institute of Molecular Medicine, Virginia Commonwealth University, Richmond, VA, 23298, USA; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.
J Mol Graph Model. 2018 Oct;85:160-170. doi: 10.1016/j.jmgm.2018.09.001. Epub 2018 Sep 6.
Glucose Regulated Protein 170 (GRP170), also called Oxygen Regulated Protein 150 (ORP150), is a major molecular chaperone resident in the endoplasmic reticulum (ER). It belongs to the heat shock protein (HSP70) super family and can be induced by conditions such as hypoxia, ischemia and interferences in calcium homeostasis. It was recently reported that GRP170 may act as a nucleotide exchange factor (NEF) for GRP78 or binding immunoglobulin protein (BiP), and the ER canonical HSP70. However, little is known about the mechanism underlying its NEF activity. In this study, two homology models of GRP170 were constructed based on the X-ray crystal structures of ADP and ATP bound HSP110, a cytosolic homolog of GRP170, in order to characterize the differences in the binding modes of both ligands. It was observed that the differences in the binding modes of ADP and ATP led to a conformation change in the substrate binding domain which could potentially influence the binding of its substrates such as BiP. Our findings help understand the effect of nucleotide binding on the function of this chaperone protein as a NEF as well as the structural differences between GRP170 and its family members.
葡萄糖调节蛋白 170（GRP170），也称为氧调节蛋白 150（ORP150），是内质网（ER）中主要的分子伴侣。它属于热休克蛋白（HSP70）超家族，可被缺氧、缺血和钙稳态干扰等条件诱导。最近有报道称，GRP170 可能作为 GRP78 或结合免疫球蛋白蛋白（BiP）和 ER 规范 HSP70 的核苷酸交换因子（NEF）发挥作用。然而，其 NEF 活性的机制知之甚少。在这项研究中，根据 ADP 和 ATP 结合 HSP110 的 X 射线晶体结构构建了两个 GRP170 的同源模型，HSP110 是 GRP170 的细胞质同源物，以表征两种配体结合模式的差异。观察到 ADP 和 ATP 的结合模式的差异导致底物结合域的构象变化，这可能会影响其底物如 BiP 的结合。我们的研究结果有助于理解核苷酸结合对这种伴侣蛋白作为 NEF 的功能的影响，以及 GRP170 与其家族成员之间的结构差异。
