5jsb | pdb_00005jsb
Crystal structure of Mcl1-inhibitor complex
Structural highlights
FunctionMCL1_HUMAN Involved in the regulation of apoptosis versus cell survival, and in the maintenance of viability but not of proliferation. Mediates its effects by interactions with a number of other regulators of apoptosis. Isoform 1 inhibits apoptosis. Isoform 2 promotes apoptosis.[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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