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

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.

SUBMITTER: Polizzi NF

PROVIDER: S-EPMC5859929 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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

Polizzi Nicholas F NF Polizzi Nicholas F NF Wu Yibing Y Lemmin Thomas T Maxwell Alison M AM Zhang Shao-Qing SQ Rawson Jeff J Beratan David N DN Therien Michael J MJ DeGrado William F WF

Nature chemistry 20170821 12

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 o ...[more]

PMID: 29168496

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