Computational design of potent and selective binders of BAK and BAX

Potent and selective binders of the key proapoptotic proteins BAK and BAX have not been described. We use computational protein design to generate high affinity binders of BAK and BAX with greater than 100-fold specificity for their target. Both binders activate their targets when at low concentration, driving pore formation, but inhibit membrane permeabilization when in excess. Crystallography shows that the BAK binder induces BAK unfolding, exposing the α6 helix and BH3 domain. Together, these data suggest that upon binding, BAK or BAX unfold; at high binder concentrations, self-association of the partially folded BAK or BAX proteins is blocked and the membrane remains intact, whereas at low concentrations, dimers form, and the membrane ruptures. Our designed binders modulate apoptosis via direct, specific interactions with BAK and BAX and reveal that for therapeutic strategies targeting BAK and BAX, inhibition requires saturating binder concentrations at the site of action.

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Publication Details

Journal
Science Advances
Published
2025-09-05
DOI
https://doi.org/10.1126/sciadv.adt4170
Primary Topic
Cell death mechanisms and regulation
Type
article
Field-Weighted Citation Impact
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article

Computational design of potent and selective binders of BAK and BAX

Rachel T. Uren, Asim K. Bera, Tiffany J. Harris, Erinna F. Lee et al.
Science Advances
Cell death mechanisms and regulation
article

Computational design of potent and selective binders of BAK and BAX

Rachel T. Uren, Asim K. Bera, Tiffany J. Harris, Erinna F. Lee, Alex Kang, S. A. Berger, Ruth M. Kluck, Peter M. Colman, David A. Baker, Sharon Tran, Richard W. Birkinshaw, Peter E. Czabotar, Mariam Lutfi, Banumathi Sankaran, Sean T. Smyth, W. Douglas Fairlie, Michelle S. Miller, Sila Kasapgil
article en

Abstract

Potent and selective binders of the key proapoptotic proteins BAK and BAX have not been described. We use computational protein design to generate high affinity binders of BAK and BAX with greater than 100-fold specificity for their target. Both binders activate their targets when at low concentration, driving pore formation, but inhibit membrane permeabilization when in excess. Crystallography shows that the BAK binder induces BAK unfolding, exposing the α6 helix and BH3 domain. Together, these data suggest that upon binding, BAK or BAX unfold; at high binder concentrations, self-association of the partially folded BAK or BAX proteins is blocked and the membrane remains intact, whereas at low concentrations, dimers form, and the membrane ruptures. Our designed binders modulate apoptosis via direct, specific interactions with BAK and BAX and reveal that for therapeutic strategies targeting BAK and BAX, inhibition requires saturating binder concentrations at the site of action.

Science AdvancesVol. 11(36)
Howard Hughes Medical Institute (US), Lawrence Berkeley National Laboratory (US), The University of Melbourne (AU), Walter and Eliza Hall Institute of Medical Research (AU), La Trobe University (AU), University of Washington (US), Olivia Newton-John Cancer Wellness & Research Centre (AU)
Openalex Percentile: Top 79%
Cell death mechanisms and regulation
DOIOpen Access PDFOpenAlex
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