4R67

Human constitutive 20S proteasome in complex with carfilzomib

4R67 の概要

• エントリーDOI: 10.2210/pdb4r67/pdb
• 関連するPDBエントリー: 1IRU 1PMA 1RYP 3UNB 3UNE 4R3O
• 関連するBIRD辞書のPRD_ID: PRD_001243
• 分子名称: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (16 entities in total)
• 機能のキーワード: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• 由来する生物種: Homo sapiens (human); 詳細
• 細胞内の位置: Cytoplasm: P60900 P49720 P49721 P28074 P20618 P28070 P25787 P25789 O14818 P28066 P25786 P25788 P28072 Q99436
• タンパク質・核酸の鎖数: 56
• 化学式量合計: 1403757.38

構造登録者

Sacchettini, J.C.,Harshbarger, W.H. (登録日: 2014-08-22, 公開日: 2015-02-11, 最終更新日: 2024-10-30)

主引用文献

Harshbarger, W.,Miller, C.,Diedrich, C.,Sacchettini, J.
Crystal Structure of the Human 20S Proteasome in Complex with Carfilzomib.
Structure, 23:418-424, 2015

PubMed Abstract: 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.

PubMed: 25599644
DOI: 10.1016/j.str.2014.11.017

実験手法

X-RAY DIFFRACTION (2.89 Å)