3zlr

Crystal structure of BCL-XL in complex with inhibitor (WEHI-539)

spinqualitylabelsall models 3zlr, resolution 2.03Å Show:Asymmetric Unit Biological Assembly Drag the structure with the mouse to rotate   Export Animated Image   Print3D Structural highlights 3zlr is a 2 chain structure with sequence from Human. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance. Ligands: EDO, SO4, X0B Related: 3zln, 3zlo, 3zk6 Resources: FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT Function [B2CL1_HUMAN] Potent inhibitor of cell death. Inhibits activation of caspases (By similarity). Appears to regulate cell death by blocking the voltage-dependent anion channel (VDAC) by binding to it and preventing the release of the caspase activator, CYC1, from the mitochondrial membrane. Also acts as a regulator of G2 checkpoint and progression to cytokinesis during mitosis. Isoform Bcl-X(S) promotes apoptosis. Publication Abstract from PubMed The prosurvival BCL-2 family protein BCL-XL is often overexpressed in solid tumors and renders malignant tumor cells resistant to anticancer therapeutics. Enhancing apoptotic responses by inhibiting BCL-XL will most likely have widespread utility in cancer treatment and, instead of inhibiting multiple prosurvival BCL-2 family members, a BCL-XL-selective inhibitor would be expected to minimize the toxicity to normal tissues. We describe the use of a high-throughput screen to discover a new series of small molecules targeting BCL-XL and their structure-guided development by medicinal chemistry. The optimized compound, WEHI-539 (7), has high affinity (subnanomolar) and selectivity for BCL-XL and potently kills cells by selectively antagonizing its prosurvival activity. WEHI-539 will be an invaluable tool for distinguishing the roles of BCL-XL from those of its prosurvival relatives, both in normal cells and notably in malignant tumor cells, many of which may prove to rely upon BCL-XL for their sustained growth. Structure-guided design of a selective BCL-X inhibitor.,Lessene G, Czabotar PE, Sleebs BE, Zobel K, Lowes KN, Adams JM, Baell JB, Colman PM, Deshayes K, Fairbrother WJ, Flygare JA, Gibbons P, Kersten WJ, Kulasegaram S, Moss RM, Parisot JP, Smith BJ, Street IP, Yang H, Huang DC, Watson KG Nat Chem Biol. 2013 Apr 21. doi: 10.1038/nchembio.1246. PMID:23603658 From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See Also B-cell lymphoma proteins 3D structures

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