Computationally designed high specificity inhibitors delineate the roles of BCL2 family proteins in cancer

2016-11-02

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

Bcl-2

Cancer

cancer biology

computational biology

computational protein design

human

systems biology

Journal Article

10.7554/eLife.20352

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.

link

eLIFE 2016; 5: e20352

eLIFE