Harshbarger Wayne, Miller Chase, Diedrich Chandler, Sacchettini James
Department of Chemistry, Texas A&M University, College Station, TX 77842-3012, USA.
Department of Biochemistry and Biophysics, Texas A&M University, College Station, TX 77842-3012, USA.
Structure. 2015 Feb 3;23(2):418-24. doi: 10.1016/j.str.2014.11.017. Epub 2015 Jan 15.
Proteasome inhibition is highly effective as a treatment for multiple myeloma, and recently carfilzomib was granted US FDA approval for the treatment of relapsed and refractory multiple myeloma. Here, we report the X-ray crystal structure of the human constitutive 20S proteasome with and without carfilzomib bound at 2.9 and 2.6 Å, respectively. Our data indicate that the S3 and S4 binding pockets play a pivotal role in carfilzomib's selectivity for chymotrypsin-like sites. Structural comparison with the mouse immunoproteasome crystal structure reveals amino acid substitutions that explain carfilzomib's slight preference for chymotrypsin-like subunits of constitutive proteasomes. In addition, comparison of the human proteasome:carfilzomib complex with the mouse proteasome:PR-957 complex reveals new details that explain why PR-957 is selective for immunoproteasomes. Together, the data presented here support the design of inhibitors for either constitutive or immunoproteasomes, with implications for the treatment of cancers as well as autoimmune and neurodegenerative diseases.
蛋白酶体抑制作为多发性骨髓瘤的一种治疗方法非常有效，最近卡非佐米已获得美国食品药品监督管理局（FDA）批准用于治疗复发和难治性多发性骨髓瘤。在此，我们报告了分别在2.9 Å和2.6 Å分辨率下结合和未结合卡非佐米的人组成型20S蛋白酶体的X射线晶体结构。我们的数据表明，S3和S4结合口袋在卡非佐米对类胰凝乳蛋白酶样位点的选择性中起关键作用。与小鼠免疫蛋白酶体晶体结构的结构比较揭示了氨基酸取代，这解释了卡非佐米对组成型蛋白酶体类胰凝乳蛋白酶样亚基的轻微偏好。此外，人蛋白酶体：卡非佐米复合物与小鼠蛋白酶体：PR - 957复合物的比较揭示了新的细节，解释了为什么PR - 957对免疫蛋白酶体具有选择性。总之，此处呈现的数据支持针对组成型或免疫蛋白酶体设计抑制剂，这对癌症以及自身免疫性和神经退行性疾病的治疗具有重要意义。
