4eu2 | pdb_00004eu2

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

spinqualitylabelsall models 4eu2, resolution 2.51Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4eu2 is a 28 chain structure with sequence from Saccharomyces cerevisiae. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: WPI Activity: Proteasome endopeptidase complex, with EC number 3.4.25.1 Resources: FirstGlance, OCA, RCSB, PDBsum Publication Abstract from PubMed 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. Homopiperazine derivatives as a novel class of proteasome inhibitors with a unique mode of proteasome binding.,Kikuchi J, Shibayama N, Yamada S, Wada T, Nobuyoshi M, Izumi T, Akutsu M, Kano Y, Sugiyama K, Ohki M, Park SY, Furukawa Y PLoS One. 2013 Apr 11;8(4):e60649. doi: 10.1371/journal.pone.0060649. Print 2013. PMID:23593271 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome

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