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Title: Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer
Authors: Berger, Stephanie;Procko, Erik;Margineantu, Daciana;Lee, Erinna F;Shen, Betty W;Zelter, Alex;Silva, Daniel-Adriano;Chawla, Kusum;Herold, Marco J;Garnier, Jean-Marc;Johnson, Richard;MacCoss, Michael J;Lessene, Guillaume;Davis, Trisha N;Stayton, Patrick S;Stoddard, Barry L;Fairlie, W Douglas;Hockenbery, David M;Baker, David
Issue Date: 2-Nov-2016
EDate: 2016-11-02
Citation: eLIFE 2016; 5: e20352
Abstract: Many 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.
DOI: 10.7554/eLife.20352
PubMed URL:
Type: Journal Article
Subjects: Bcl-2
cancer biology
computational biology
computational protein design
systems biology
Appears in Collections:Journal articles

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