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De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy.

Publication ,  Journal Article
Polizzi, NF; Wu, Y; Lemmin, T; Maxwell, AM; Zhang, S-Q; Rawson, J; Beratan, DN; Therien, MJ; DeGrado, WF
Published in: Nature chemistry
December 2017

Protein catalysis requires the atomic-level orchestration of side chains, substrates and cofactors, and yet the ability to design a small-molecule-binding protein entirely from first principles with a precisely predetermined structure has not been demonstrated. Here we report the design of a novel protein, PS1, that binds a highly electron-deficient non-natural porphyrin at temperatures up to 100 °C. The high-resolution structure of holo-PS1 is in sub-Å agreement with the design. The structure of apo-PS1 retains the remote core packing of the holoprotein, with a flexible binding region that is predisposed to ligand binding with the desired geometry. Our results illustrate the unification of core packing and binding-site definition as a central principle of ligand-binding protein design.

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Published In

Nature chemistry

DOI

EISSN

1755-4349

ISSN

1755-4330

Publication Date

December 2017

Volume

9

Issue

12

Start / End Page

1157 / 1164

Related Subject Headings

  • Temperature
  • Proteins
  • Porphyrins
  • Organic Chemistry
  • Models, Molecular
  • Ligands
  • 34 Chemical sciences
  • 03 Chemical Sciences
 

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Polizzi, N. F., Wu, Y., Lemmin, T., Maxwell, A. M., Zhang, S.-Q., Rawson, J., … DeGrado, W. F. (2017). De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy. Nature Chemistry, 9(12), 1157–1164. https://doi.org/10.1038/nchem.2846
Polizzi, Nicholas F., Yibing Wu, Thomas Lemmin, Alison M. Maxwell, Shao-Qing Zhang, Jeff Rawson, David N. Beratan, Michael J. Therien, and William F. DeGrado. “De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy.Nature Chemistry 9, no. 12 (December 2017): 1157–64. https://doi.org/10.1038/nchem.2846.
Polizzi NF, Wu Y, Lemmin T, Maxwell AM, Zhang S-Q, Rawson J, et al. De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy. Nature chemistry. 2017 Dec;9(12):1157–64.
Polizzi, Nicholas F., et al. “De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy.Nature Chemistry, vol. 9, no. 12, Dec. 2017, pp. 1157–64. Epmc, doi:10.1038/nchem.2846.
Polizzi NF, Wu Y, Lemmin T, Maxwell AM, Zhang S-Q, Rawson J, Beratan DN, Therien MJ, DeGrado WF. De novo design of a hyperstable non-natural protein-ligand complex with sub-Å accuracy. Nature chemistry. 2017 Dec;9(12):1157–1164.

Published In

Nature chemistry

DOI

EISSN

1755-4349

ISSN

1755-4330

Publication Date

December 2017

Volume

9

Issue

12

Start / End Page

1157 / 1164

Related Subject Headings

  • Temperature
  • Proteins
  • Porphyrins
  • Organic Chemistry
  • Models, Molecular
  • Ligands
  • 34 Chemical sciences
  • 03 Chemical Sciences