Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1
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elife-25541-v1.pdf
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3.14 MB
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Author(s)
Ryan, Jeremy A.
Letai, Anthony
Jenson, Justin Michael
Grant, Robert A.
Keating, Amy E.
Date Issued
June 2017
Journal
eLife
Publisher
eLife Sciences Publications, Ltd
Citation
Jenson, Justin M et al. “Epistatic Mutations in PUMA BH3 Drive an Alternate Binding Mode to Potently and Selectively Inhibit Anti-Apoptotic Bfl-1.” eLife 2017, 6 (June 2017): e25541 © Jenson et al
Version
Final published version
Abstract
Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry, relative to PUMA and other binding partners, due to a set of epistatic mutations. FS2 modified with an electrophile reacts with a cysteine near the peptide-binding groove to augment specificity. Designed Bfl-1 binders provide reagents for cellular profiling and leads for developing enhanced and cell-permeable peptide or small-molecule inhibitors.
MIT Department
Massachusetts Institute of Technology. Department of Biological Engineering
Massachusetts Institute of Technology. Department of Biology
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Creative Commons Attribution 4.0 International License
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DOI of Published Version
https://doi.org/10.7554/ELIFE.25541
