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STRUCTURAL BIOLOGY

First prediction of sequence-specific recognition of double-helix nucleic acids by proteins

Nature Reviews Molecular Cell Biology volume 23, page 166 (2022)Cite this article

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“Imagination is more important than knowledge.” This Albert Einstein quote certainly applies to a study by Seeman, Rosenberg and Rich published in the Proc. Natl Acad. Sci. USA in 1976. With knowledge of the crystal structures of DNA and RNA dinucleotide mini-duplexes and of transfer RNA (tRNAPhe) and with information from nucleic acids fibre diffraction studies in hand, but five years before the introduction of the first crystal structure of a DNA–protein complex, they pondered the question: how can proteins recognize specific sequences in double-helix nucleic acids? Specifically, they considered the unique identification of the four possible base pairs A•U(T), U(T)•A, G•C and C•G by protein side chains.

Seeman and colleagues correctly assumed that the duplex backbones will serve as a frame of reference from which to probe the information in the major and minor grooves. Hydrogen bonds would serve as the key mediator of DNA–protein interactions, unlike hydrophobic contacts or stacking. By comparing the stereochemistry of base pair steps, they identified six potential recognition sites along base pair edges in the major groove and another three sites in the minor groove. Careful analysis of the ways to discriminate between base pairs using these sites led to the conclusion that a single hydrogen bond would not allow distinction between sequences with sufficient precision.

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References

Original article

  • Seeman, N. C. et al. Sequence-specific recognition of double-helical nucleic acids by proteins. Proc. Natl Acad. Sci. USA 73, 804–808 (1976)

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Related articles

  • Wilds, C. J. et al. Direct observation of a cytosine analogue that forms five hydrogen bonds to guanosine: guanidino G-clamp. Angew. Chem. Int. Ed. 41, 115–117 (2002)

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  • Ball, P. Obituary Ned Seeman (1945–2021). Nanotechnologist who built the first self-assembling DNA structures. Nature 600, 605 (2021)

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Authors and Affiliations

  1. Department of Biochemistry, Vanderbilt University, Nashville, TN, USA

    Martin Egli

  2. Media Lab, Massachusetts Institute of Technology, Cambridge, MA, USA

    Shuguang Zhang

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  1. Martin Egli
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  2. Shuguang Zhang
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Correspondence to Martin Egli or Shuguang Zhang.

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Egli, M., Zhang, S. First prediction of sequence-specific recognition of double-helix nucleic acids by proteins. Nat Rev Mol Cell Biol 23, 166 (2022). https://doi.org/10.1038/s41580-022-00451-4

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  • DOI: https://doi.org/10.1038/s41580-022-00451-4

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