Heteromeric three-stranded coiled coils designed using a Pb(ii)(Cys)3 template mediated strategy

Audrey E. Tolbert, Catherine S. Ervin, Leela Ruckthong, Thomas J. Paul, Vindi M. Jayasinghe-Arachchige, Kosh P. Neupane, Jeanne A. Stuckey, Rajeev Prabhakar, Vincent L. Pecoraro

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Three-stranded coiled coils are peptide structures constructed from amphipathic heptad repeats. Here we show that it is possible to form pure heterotrimeric three-stranded coiled coils by combining three distinct characteristics: (1) a cysteine sulfur layer for metal coordination, (2) a thiophilic, trigonal pyramidal metalloid (Pb(ii)) that binds to these sulfurs and (3) an adjacent layer of reduced steric bulk generating a cavity where water can hydrogen bond to the cysteine sulfur atoms. Cysteine substitution in an a site yields Pb(ii)A2B heterotrimers, while d sites provide pure Pb(ii)C2D or Pb(ii)CD2 scaffolds. Altering the metal from Pb(ii) to Hg(ii) or shifting the relative position of the sterically less demanding layer removes heterotrimer specificity. Because only two of the eight or ten hydrophobic layers are perturbed, catalytic sites can be introduced at other regions of the scaffold. A Zn(ii)(histidine)3(H2O) centre can be incorporated at a remote location without perturbing the heterotrimer selectivity, suggesting a unique strategy to prepare dissymmetric catalytic sites within self-assembling de novo-designed proteins.

Original languageEnglish (US)
Pages (from-to)405-411
Number of pages7
JournalNature Chemistry
Volume12
Issue number4
DOIs
StatePublished - Apr 1 2020

ASJC Scopus subject areas

  • Chemistry(all)
  • Chemical Engineering(all)

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    Tolbert, A. E., Ervin, C. S., Ruckthong, L., Paul, T. J., Jayasinghe-Arachchige, V. M., Neupane, K. P., Stuckey, J. A., Prabhakar, R., & Pecoraro, V. L. (2020). Heteromeric three-stranded coiled coils designed using a Pb(ii)(Cys)3 template mediated strategy. Nature Chemistry, 12(4), 405-411. https://doi.org/10.1038/s41557-020-0423-6