Crystal Structure of the Human 20S Proteasome in Complex with Carfilzomib
Crystal Structure of the Human 20S Proteasome in Complex with Carfilzomib
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DOI：
10.1016/j.str.2014.11.017
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发表时间：
2015-02-03
期刊：
影响因子：
5.7
通讯作者：
Sacchettini, James
中科院分区：
文献类型：
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作者：
Harshbarger, Wayne;Miller, Chase;Sacchettini, James
蛋白酶体抑制治疗多发性骨髓瘤非常有效，最近卡菲佐米被美国FDA批准用于治疗复发和难治性多发性骨髓瘤。在这里，我们报告了含有和不含有carfilzomib的人结构性20S蛋白酶体的X射线晶体结构，分别为2.9埃和2.6埃。我们的数据表明，S3和S4结合口袋在carfilzomib对胰凝乳蛋白酶样位点的选择性中起着关键作用。与小鼠免疫蛋白酶体晶体结构的比较显示，氨基酸替代解释了Carfilzomib对组成蛋白酶体的类糜蛋白酶样亚单位的轻微偏好。此外，人类蛋白酶体：carfilzomib复合体与小鼠蛋白酶体：PR-957复合体的比较揭示了新的细节，解释了PR-957对免疫蛋白酶体具有选择性的原因。总之，这里提供的数据支持针对结构性或免疫蛋白酶体的抑制剂的设计，这对癌症以及自身免疫性和神经退行性疾病的治疗具有意义。
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 angstrom, 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.