5jsn | pdb_00005jsn
Bcl2-inhibitor complex
Structural highlights
DiseaseBCL2_HUMAN Note=A chromosomal aberration involving BCL2 has been found in chronic lymphatic leukemia. Translocation t(14;18)(q32;q21) with immunoglobulin gene regions. BCL2 mutations found in non-Hodgkin lymphomas carrying the chromosomal translocation could be attributed to the Ig somatic hypermutation mechanism resulting in nucleotide transitions. FunctionBCL2_HUMAN Suppresses apoptosis in a variety of cell systems including factor-dependent lymphohematopoietic and neural cells. Regulates cell death by controlling the mitochondrial membrane permeability. Appears to function in a feedback loop system with caspases. Inhibits caspase activity either by preventing the release of cytochrome c from the mitochondria and/or by binding to the apoptosis-activating factor (APAF-1).[1] Publication Abstract from PubMedMany cancers overexpress one or more of the six human pro-survival BCL2 family proteins to evade apoptosis. To determine which BCL2 protein or proteins block apoptosis in different cancers, we computationally designed three-helix bundle protein inhibitors specific for each BCL2 pro-survival protein. Following in vitro optimization, each inhibitor binds its target with high picomolar to low nanomolar affinity and at least 300-fold specificity. Expression of the designed inhibitors in human cancer cell lines revealed unique dependencies on BCL2 proteins for survival which could not be inferred from other BCL2 profiling methods. Our results show that designed inhibitors can be generated for each member of a closely-knit protein family to probe the importance of specific protein-protein interactions in complex biological processes. Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer.,Berger S, Procko E, Margineantu D, Lee EF, Shen BW, Zelter A, Silva DA, Chawla K, Herold MJ, Garnier JM, Johnson R, MacCoss MJ, Lessene G, Davis TN, Stayton PS, Stoddard BL, Fairlie WD, Hockenbery DM, Baker D Elife. 2016 Nov 2;5. pii: e20352. doi: 10.7554/eLife.20352. PMID:27805565[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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