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Nat Chem. 2017 Dec;9(12):1157-1164. doi: 10.1038/nchem.2846. Epub 2017 Aug 21.

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

Author information

1
Department of Biochemistry, Duke University, Durham, North Carolina 27710, USA.
2
Department of Pharmaceutical Chemistry, Cardiovascular Research Institute, University of California, San Francisco, California 94158, USA.
3
Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
4
Department of Physics, Duke University, Durham, North Carolina 27708, USA.

Abstract

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.

PMID:
29168496
PMCID:
PMC5859929
DOI:
10.1038/nchem.2846
[Indexed for MEDLINE]
Free PMC Article

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