ArticleJournal of molecular biology2013
Structure-based redesign of the binding specificity of anti-apoptotic Bcl-x(L).
Article in Journal of molecular biology, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 17 papers.
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Who cites it
17 citing papers in PubMed.
- Modifying inhibitor specificity for homologous enzymes by machine learning.The FEBS journal · 2026Article
- Contingency and chance erase necessity in the experimental evolution of ancestral proteins.eLife · 2021Article
- Selective Affimers Recognise the BCL-2 Family Proteins BCL-xChembiochem : a European journal of chemical biology · 2021Article
- Multi-input chemical control of protein dimerization for programming graded cellular responses.Nature biotechnology · 2019Article
- Peptide design by optimization on a data-parameterized protein interaction landscape.Proceedings of the National Academy of Sciences of the United States of America · 2018Article
- Article
- Enriching Peptide Libraries for Binding Affinity and Specificity Through Computationally Directed Library Design.Methods in molecular biology (Clifton, N.J.) · 2017Article
- Protein stability: computation, sequence statistics, and new experimental methods.Current opinion in structural biology · 2015Review
- Locating Herpesvirus Bcl-2 Homologs in the Specificity Landscape of Anti-Apoptotic Bcl-2 Proteins.Journal of molecular biology · 2015Article
- SwiftLib: rapid degenerate-codon-library optimization through dynamic programming.Nucleic acids research · 2015Article
- Design, synthesis and evaluation of marinopyrrole derivatives as selective inhibitors of Mcl-1 binding to pro-apoptotic Bim and dual Mcl-1/Bcl-xL inhibitors.European journal of medicinal chemistry · 2015Article
- The functional differences between pro-survival and pro-apoptotic B cell lymphoma 2 (Bcl-2) proteins depend on structural differences in their Bcl-2 homology 3 (BH3) domains.The Journal of biological chemistry · 2014Article
- Article
- Control of apoptosis by the BCL-2 protein family: implications for physiology and therapy.Nature reviews. Molecular cell biology · 2014Review
- New insights into the interdependence between amino acid stereochemistry and protein structure.Biophysical journal · 2013Article
- Strategies to control the binding mode of de novo designed protein interactions.Current opinion in structural biology · 2013Review
- Peptide ligands for pro-survival protein Bfl-1 from computationally guided library screening.ACS chemical biology · 2013Article
Corrections and comments
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Authors and funding
3 authors.
Funding
Abstract
Many native proteins are multi-specific and interact with numerous partners, which can confound analysis of their functions. Protein design provides a potential route to generating synthetic variants of native proteins with more selective binding profiles. Redesigned proteins could be used as research tools, diagnostics or therapeutics. In this work, we used a library screening approach to reengineer the multi-specific anti-apoptotic protein Bcl-x(L) to remove its interactions with many of its binding partners, making it a high-affinity and selective binder of the BH3 region of pro-apoptotic protein Bad. To overcome the enormity of the potential Bcl-x(L) sequence space, we developed and applied a computational/experimental framework that used protein structure information to generate focused combinatorial libraries. Sequence features were identified using structure-based modeling, and an optimization algorithm based on integer programming was used to select degenerate codons that maximally covered these features. A constraint on library size was used to ensure thorough sampling. Using yeast surface display to screen a designed library of Bcl-x(L) variants, we successfully identified a protein with ~1000-fold improvement in binding specificity for the BH3 region of Bad over the BH3 region of Bim. Although negative design was targeted only against the BH3 region of Bim, the best redesigned protein was globally specific against binding to 10 other peptides corresponding to native BH3 motifs. Our design framework demonstrates an efficient route to highly specific protein binders and may readily be adapted for application to other design problems.
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Registered trials
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