Computational design of potent and selective binders of BAK and BAX

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

doi:10.1126/sciadv.adt4170

Computational design of potent and selective binders of BAK and BAX

Journal Article · Fri Sep 05 00:00:00 EDT 2025 · Science Advances

DOI:https://doi.org/10.1126/sciadv.adt4170· OSTI ID:2997773

^[1]; Lee, Erinna F. ^[2]; Harris, Tiffany J. ^[3]; ^[4]; ^[1]; ^[1]; ^[1]; ^[5]; Kasapgil, Sila ^[6]; ^[7]; ^[6]; Lutfi, Mariam ^[6]; ^[7]; ^[7]; Colman, Peter M. ^[7]; Fairlie, Walter D. ^[2]; ^[7]; ^[1]; ^[7]

Univ. of Washington, Seattle, WA (United States)
La Trobe Univ., Melbourne, VIC (Australia); Olivia Newton-John Cancer Research Institute, Heidelberg, VIC (Australia)
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC (Australia)
Olivia Newton-John Cancer Research Institute, Heidelberg, VIC (Australia); La Trobe Univ., Melbourne, VIC (Australia)
Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC (Australia)
Walter and Eliza Hall Institute of Medical Research, Parkville, VIC (Australia); Univ. of Melbourne, Parkville, VIC (Australia)

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities (SUF); USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 2997773

Journal Information:: Science Advances, Journal Name: Science Advances Journal Issue: 36 Vol. 11; ISSN 2375-2548

Publisher:: American Association for the Advancement of Science (AAAS)Copyright Statement

Country of Publication:: United States

Language:: English

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