4qlq

yCP in complex with tripeptidic epoxyketone inhibitor 8

spinqualitylabelsall models 4qlq, resolution 2.40Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 4qlq is a 20 chain structure with sequence from Saccharomyces cerevisiae S288C. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Method: X-ray diffraction, Resolution 2.4Å Ligands: 38N, MES, MG Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function PSA3_YEAST The proteasome degrades poly-ubiquitinated proteins in the cytoplasm and in the nucleus. It is essential for the regulated turnover of proteins and for the removal of misfolded proteins. The proteasome is a multicatalytic proteinase complex that is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH. It has an ATP-dependent proteolytic activity. Publication Abstract from PubMed Mammalian genomes encode seven catalytic proteasome subunits, namely, beta1c, beta2c, beta5c (assembled into constitutive 20S proteasome core particles), beta1i, beta2i, beta5i (incorporated into immunoproteasomes), and the thymoproteasome-specific subunit beta5t. Extensive research in the past decades has yielded numerous potent proteasome inhibitors including compounds currently used in the clinic to treat multiple myeloma and mantle cell lymphoma. Proteasome inhibitors that selectively target combinations of beta1c/beta1i, beta2c/beta2i, or beta5c/beta5i are available, yet ligands truly selective for a single proteasome activity are scarce. In this work we report the development of cell-permeable beta1i and beta5i selective inhibitors that outperform existing leads in terms of selectivity and/or potency. These compounds are the result of a rational design strategy using known inhibitors as starting points and introducing structural features according to the X-ray structures of the murine constitutive and immunoproteasome 20S core particles. Structure-Based Design of beta1i or beta5i Specific Inhibitors of Human Immunoproteasomes.,de Bruin G, Huber EM, Xin BT, van Rooden EJ, Al-Ayed K, Kim KB, Kisselev AF, Driessen C, van der Stelt M, van der Marel GA, Groll M, Overkleeft HS J Med Chem. 2014 Jul 15. PMID:25006746 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also Proteasome 3D structures

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