4EU2

Crystal structure of 20s proteasome with novel inhibitor K-7174

Summary for 4EU2

• Entry DOI: 10.2210/pdb4eu2/pdb
• Descriptor: Proteasome component C7-alpha, Proteasome component PUP3, Proteasome component C11, ... (16 entities in total)
• Functional Keywords: proteasome inhibitor, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Saccharomyces cerevisiae (Baker's yeast); More
• Cellular location: Cytoplasm: P21243 P25451 P22141 P30656 P23724 P30657 P23639 P23638 P40303 P32379 P40302 P21242 P38624 P25043
• Total number of polymer chains: 28
• Total formula weight: 707188.29

Authors

Kikuchi, J.,Shibayama, N.,Yamada, S.,Wada, T.,Nobuyoshi, M.,Izumi, T.,Akutsu, M.,Kano, Y.,Ohki, M.,Sugiyama, K.,Park, S.-Y.,Furukawa, Y. (deposition date: 2012-04-25, release date: 2013-05-01, Last modification date: 2024-03-20)

Primary citation

Kikuchi, J.,Shibayama, N.,Yamada, S.,Wada, T.,Nobuyoshi, M.,Izumi, T.,Akutsu, M.,Kano, Y.,Sugiyama, K.,Ohki, M.,Park, S.Y.,Furukawa, Y.
Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.
Plos One, 8:e60649-e60649, 2013

PubMed Abstract: The proteasome is a proteolytic machinery that executes the degradation of polyubiquitinated proteins to maintain cellular homeostasis. Proteasome inhibition is a unique and effective way to kill cancer cells because they are sensitive to proteotoxic stress. Indeed, the proteasome inhibitor bortezomib is now indispensable for the treatment of multiple myeloma and other intractable malignancies, but is associated with patient inconvenience due to intravenous injection and emerging drug resistance. To resolve these problems, we attempted to develop orally bioavailable proteasome inhibitors with distinct mechanisms of action and identified homopiperazine derivatives (HPDs) as promising candidates. Biochemical and crystallographic studies revealed that some HPDs inhibit all three catalytic subunits (ß 1, ß 2 and ß 5) of the proteasome by direct binding, whereas bortezomib and other proteasome inhibitors mainly act on the ß5 subunit. Proteasome-inhibitory HPDs exhibited cytotoxic effects on cell lines from various hematological malignancies including myeloma. Furthermore, K-7174, one of the HPDs, was able to inhibit the growth of bortezomib-resistant myeloma cells carrying a ß5-subunit mutation. Finally, K-7174 had additive effects with bortezomib on proteasome inhibition and apoptosis induction in myeloma cells. Taken together, HPDs could be a new class of proteasome inhibitors, which compensate for the weak points of conventional ones and overcome the resistance to bortezomib.

PubMed: 23593271
DOI: 10.1371/journal.pone.0060649

Experimental method

X-RAY DIFFRACTION (2.509 Å)