4R67

Human constitutive 20S proteasome in complex with carfilzomib

Summary for 4R67

• Entry DOI: 10.2210/pdb4r67/pdb
• Related: 1IRU 1PMA 1RYP 3UNB 3UNE 4R3O
• Related PRD ID: PRD_001243
• Descriptor: Proteasome subunit alpha type-6, Proteasome subunit beta type-3, Proteasome subunit beta type-2, ... (16 entities in total)
• Functional Keywords: hydrolase, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Homo sapiens (human); More
• Cellular location: Cytoplasm: P60900 P49720 P49721 P28074 P20618 P28070 P25787 P25789 O14818 P28066 P25786 P25788 P28072 Q99436
• Total number of polymer chains: 56
• Total formula weight: 1403757.38

Authors

Sacchettini, J.C.,Harshbarger, W.H. (deposition date: 2014-08-22, release date: 2015-02-11, Last modification date: 2024-10-30)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.89 Å)