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De novo design of a hyperstable non-natural protein–ligand complex with sub-Å accuracy
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De novo design of a hyperstable non-natural protein–ligand complex with sub-Å accuracy
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De novo design of a hyperstable non-natural protein–ligand complex with sub-Å accuracy
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Journal Article
De novo design of a hyperstable non-natural protein–ligand complex with sub-Å accuracy
2017
Overview
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.
The first demonstration of a protein designed entirely from first principles that binds a small-molecule cofactor in a precisely predetermined orientation has now been described. The design method utilizes a remote protein core that both anchors and predisposes a flexible binding site for the desired cofactor-binding geometry.
