Computationally Designed Peptide Inhibitors of the Ubiquitin E3 Ligase SCFFbx4

Authors

  • Junglim Lee,

    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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    • These authors contributed equally to this work.

  • Dr. Deanne W. Sammond,

    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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    • These authors contributed equally to this work.

  • Zeno Fiorini,

    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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  • Dr. Jonel P. Saludes,

    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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  • Dr. Michael G. Resch,

    1. National Renewable Energy Laboratory, 15013 Denver West Parkway, Golden, CO 80401 (USA)
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  • Prof. Dr. Bing Hao,

    1. Molecular, Microbial and Structural Biology, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, CT 06030 (USA)
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  • Dr. Wei Wang,

    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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  • Prof. Dr. Hang Yin,

    Corresponding author
    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
    • Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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  • Prof. Dr. Xuedong Liu

    Corresponding author
    1. Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
    • Department of Chemistry and Biochemistry, 596 UCB, University of Colorado, JSCBB 3415 Colorado Avenue, Boulder, Colorado 80309-0215 (USA)
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Abstract

original image

A structure-based computational approach was used to rationally design peptide inhibitors that can target an E3 ligase (SCFFbx4)–substrate (TRF1) interface and subsequent ubiquitylation. Characterization of the inhibitors demonstrates that our sequence-optimization protocol results in an increase in peptide–TRF1 affinity without compromising peptide–protein specificity.

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